Skip Navigation

Cardiovascular Research 2000 46(3):403-411; doi:10.1016/S0008-6363(00)00023-7
© 2000 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Scotland, R. S.
Right arrow Articles by Ahluwalia, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scotland, R. S.
Right arrow Articles by Ahluwalia, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2000, European Society of Cardiology

Endogenous factors involved in regulation of tone of arterial vasa vasorum: implications for conduit vessel physiology

Ramona S. Scotland*, Patrick J.T. Vallance and Amrita Ahluwalia

Centre for Clinical Pharmacology, University College London, The Rayne Institute, 5 University St., London WC1E 6JJ, UK

* Corresponding author. Tel.: +44-171-209-6606; fax: +44-171-209-6212 r.scotland{at}ucl.ac.uk

Received 14 September 1999; accepted 13 January 2000


   Abstract
Top
 Abstract
1 Morphology
 2 Regulation of blood...
 3 Role of vasa...
 4 Conclusion
 References
 
The walls of conduit blood vessels are nourished by diffusion of oxygen from luminal blood and from the vasa vasorum. The vasa vasorum, or ‘vessels of a vessel’, form a network of microvessels that lie in the adventitia and penetrate the outer media of the host vessel wall. Although the importance of the vasa vasorum in providing nutritional support is not well defined, obstruction of blood flow through these vessels has been implicated in the pathogenesis of certain cardiovascular diseases including atherosclerosis. This review focuses on the mechanisms that regulate tone in the vasa vasorum of large arteries and the functional implications of changes in reactivity of vasa vasorum.

KEYWORDS Arteries; Atherosclerosis; Blood flow; Capillaries; Restenosis


   1 Morphology
Top
 Abstract
 1 Morphology
2 Regulation of blood...
 3 Role of vasa...
 4 Conclusion
 References
 
The morphology of the vasa vasorum is critical in understanding the mechanisms by which these vessels regulate their tone. This is supported by the fact that the distribution of vasa changes in certain vascular diseases and varies between vascular beds as well as within any single blood vessel, as with the aorta. This striking plasticity may relate directly to a flexibility in their function according to environmental conditions.

The vasa vasorum surrounds and penetrates the adventitia and outer media of large arteries and veins including aorta, vena cava, coronary, femoral, carotid and some intracerebral arteries [1]. The vasa vasorum itself consists of a network of small arteries typically flanked by two small veins, providing an entire microvascular bed within the wall of the host blood vessel [2]. Capillary vessels have also been noted in the vasa vasorum although in some cases they are short enough to constitute arteriovenous shunts [2]. Vasa can originate from several different sites. For example, vasa in the ascending aorta arise from coronary and brachiocephalic arteries; vasa in the descending thoracic aorta originate from the intercostal arteries; and vasa in the abdominal aorta may arise from the lumbar and mesenteric arteries and from the lumen of the aorta itself. Large veins are also supplied by vasa, the vasa venarum, which lie in the adventitia and penetrate the media. In some veins, the vasa venarum extends to the intima [3] indicating that these microvessels have a more important role in nutrition of the walls of veins than arteries. The source of the vasa venarum is also arterial and arises from branchpoints of adjacent arteries. Similar to the vasa vasorum, the vasa venarum consists of a network of small arteries and veins. It has been suggested that the venules of the vasa venarum emerge from the adventitia and empty into adjacent veins rather than into the lumen of the parent vessel [4].

There are two anatomically distinct patterns of vasa; first order vasa run longitudinally to the lumen of the host vessel; while second order vasa are arranged circumferentially around the host vessel [5]. Arterial vasa are readily distinguishable from venous vasa since they have a straight course whereas the course of venous vasa is more tortuous [2]. In addition, arterial vasa are less numerous with fewer branches and have a smaller lumen than the small veins. Fig. 1 shows an arterial vasa at the adventitial–medial border of a porcine thoracic aorta. It is clear that these microvessels consist of layers of smooth muscle oriented radially around a single layer of endothelium [6], indicating that these vessels have the capacity to regulate tone.


Figure 1
View larger version (58K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Haematoxylin and eosin staining of porcine thoracic aorta demonstrating an arterial vasa at the adventitial (ADV)–medial (MED) border.

 
Like other small resistance arteries, arterial vasa are neuronally innervated. Fig. 2a shows an isolated porcine vasa labelled with antibody to general neural marker protein product 9.5 (PGP 9.5). These nerves appear to be sympathetic fibres since they stain heavily anti-neuropeptide Y (NPY) (Fig. 2b). Similarly, the vasa vasorum of the human saphenous vein is densely innervated by unmyelinated sympathetic nerve fibres [7] and NPY, vasoactive intestinal peptide (VIP) and dopamine β-hydroxylase-immunoreactive nerves have also been demonstrated to supply the vasa vasorum of deep dorsal penile vein [8]. Although the neural innervation of vasa is mainly sympathetic, other nerve types are also present in some vasa vasorum. For example, calcitonin gene-related peptide (CGRP) and substance P (SP)-containing nerves have been demonstrated around the vasa vasorum of human saphenous vein [7] and rat carotid arteries [9].


Figure 2
View larger version (93K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Whole mount indirect immunofluorescence (yellow) of isolated porcine thoracic aortic vasa vasorum (red) incubated with (A) anti-protein gene product 9.5 (PGP 9.5) and (B) anti-neuropeptide Y (NPY).

 
The presence of the vasa vasorum in blood vessels is likely to be related to nutritional needs. Comparison of different species revealed that vasa are present in the media of the aorta of those animals in which the aortic wall thickness exceeds 0.5 mm [10], or as redefined by Wolinsky and Glagov [11], when aortic thickness exceeds 29 lamellae. Indeed if one considers the aorta, in those species where the aorta has less than 29 lamellae the vasa vasorum is absent from the media, whereas in the aorta of large animals the inner 29 lamellae are avascular and the outer lamellae are supplied by the vasa vasorum. Consistent with this definition, the media of human abdominal aorta has 28 lamellae and is avascular. Interestingly, the avascular regions of the abdominal aorta also show the greatest propensity for atherosclerosis [11], implying that the blood supply provided by the vasa vasorum may be protective in this respect. Therefore, one could speculate that if the vasa vasorum are important in providing protection of the host vessel, decreases in blood flow through these microvessels may contribute to atherosclerosis. Coronary arteries are an exception to the above definitions since the critical wall thickness is less in coronary arteries (0.35 mm) than in the aorta [10]. This anomaly suggests that the above definition may not hold true for all vessels and that as well as wall thickness, an important determinant for the presence of vasa vasorum may be luminal oxygen tension. In support of this are the findings that large veins, which have thin walls but low luminal oxygen tension, are supplied by a dense network of vasa and that vasa vasorum of the canine aorta dilate in response to acute systemic hypoxia [12]. This latter response may represent an important mechanism whereby the supply of oxygen to a blood vessel wall is increased when diffusion of oxygen from the lumen is limited. Similar to veins, the pulmonary artery, which also has low luminal oxygen tension, has a more extensive supply of vasa vasorum in the adventitia and outer media than systemic arteries [13]. Indeed measurement of blood flow to canine pulmonary artery is equal to that to the aorta despite a difference in wall thickness and lamellar units (29 compared to 49) [12]. Therefore, both oxygen tension and wall thickness appear to be important determinants of the presence of vasa. This may have important implications for the host vessel in diseases that result in increases in wall thickness or hypoxia (see later) since the distribution of the vasa is not fixed. It is clear that in certain cardiovascular diseases (see later), including atherosclerosis, the number and density of vasa changes and it seems that this relates closely to changes in blood supply to the conduit vessel wall.


   2 Regulation of blood flow
Top
 Abstract
 1 Morphology
 2 Regulation of blood...
3 Role of vasa...
 4 Conclusion
 References
 
The presence of several layers of smooth muscle implies that the vessels of the vasa vasorum actively regulate their own tone rather than serving as a passive channel for blood flow. The first studies supporting this hypothesis investigated vasa vasorum reactivity to vasoactive agents in dogs in vivo [14]. This study exploited the microsphere technique in which microspheres labelled with gamma-emitting isotopes were injected into the left atria, distributed throughout the circulation and, since they are too large to pass through capillaries, extracted following a single passage through the vasa vasorum. The results of this study suggested that the diameter of the vasa vasorum of canine thoracic aorta increased in response to intravenous infusion of adenosine [14]. In contrast another study using the same technique showed no change in blood flow through the vasa vasorum of carotid arteries of monkeys during infusion of either the vasoconstrictor phenylephrine (PE) or 5-hydroxytryptamine (5-HT) [15]. Ohhira and Ohhashi [16] removed sections of the vasa vasorum attached to the canine thoracic aorta and examined the reactivity of the vasa vasorum in vitro by measurement of perfusion pressure. In this study the vasa vasorum appeared sensitive to a range of constrictor agents: 5-HT>>noradrenaline (NA)=adrenaline>>dopamine. Indeed, in vitro receptor autoradiography has demonstrated dense binding of [3H]-5-HT in the vasa vasorum of human saphenous vein [17]. Whilst these studies appear to support the hypothesis that the vasa vasorum regulates its own tone, in both systems vasa reactivity was not studied in isolation. The possibility that the responses seen were secondary to effects on the host vessel and not direct effects of the agonists on the vascular smooth muscle of the vasa vasorum cannot be excluded in these studies. More recently, however, clear evidence of vasa vasorum reactivity has been provided by studies of these vessels in isolation using the tension myography technique [6]. This study showed that isolated porcine vasa contract to a range of constrictors. Interestingly, the profile of vasoconstrictor reactivity of the isolated vasa is quite different from other small arteries, in that, whilst endothelin-1 (ET-1) produced potent concentration-dependent contractions (see Fig. 3) the vasa appear to be relatively insensitive to NA, thromboxane A2 (TXA2) mimetics and angiotensin II (AngII). A similar profile of reactivity was also seen in vasa isolated from bovine aortic arch and therefore is likely to represent a general pattern of reactivity of isolated arterial vasa of the aorta. These data show clearly that the vasa vasorum can respond to vasoconstrictors and support the hypothesis that these vessels regulate their own tone independently of the host vessel. Although the functional significance of this unusual reactivity is not known, we hypothesize that this may represent a mechanism whereby the vasa vasorum is protected from the constrictor effects of TXA2 released from activated platelets or NA released from sustained sympathetic activity. Such a resistance to these constrictors would maintain vasa patency despite the presence of substances that constrict the host vessel.


Figure 3
View larger version (5K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Typical contractile response of isolated porcine thoracic aortic vasa (normalised diameter ~150 µm) to endothelin-1 (ET-1, 0.1–500 nM) mounted in a tension myograph.

 
ET-1 produces concentration-related contraction of isolated vasa with a similar potency to that reported in other porcine [18] and human small arteries [19]. Circulating levels of ET-1 are typically low. However, studies on forearm blood flow in humans using ET receptor antagonists indicate that ET-1 has a role in local regulation of basal tone [20], suggesting that basal levels of ET-1 may be sufficient to directly affect tone in vasa vasorum. Characterisation of the contractile responses to ET-1 in vasa vasorum has identified the presence of both ETA and ETB receptor subtypes [21]. ET-1, at low concentrations, also sensitizes arterial vasa to the constrictor effects of NA; such that in the presence of ET-1 the maximum contraction to NA increases 4-fold, an effect that is abolished by inhibition of L-type calcium channels [21]. This sensitisation by ET-1 is not a phenomenon exclusive to the vasa vasorum but has been reported to occur in other resistance arteries from several species including isolated human [22,23], rat [24,25] and canine [26] resistance arteries. Partial depolarization of vasa smooth muscle with K+ (10–20 mM) also significantly potentiates the responses to NA and TXA2-mimetic. The functional significance of these effects is unclear but the findings suggest that an increase in ET-1 levels, a feature of certain cardiovascular diseases, would render vasa vasorum reactive to NA and that slight depolarization of smooth muscle would enhance responses to both NA and TXA2. Consistent with these observations, in a study using monkeys fed an atherogenic diet, a model associated with elevated ET-1 levels [27], the diameter of vasa vasorum of coronary arteries decreased in response to PE or 5-HT whilst these constrictors had no effect in healthy animals [15]. The reactivity of vasa vasorum to ET-1 and the considerable [125I]ET-1 binding to the vasa vasorum of both human saphenous vein and porcine femoral arteries suggest that ET-1 may have an important role in regulating nutrient blood flow through the vasa vasorum, particularly in situations such as atherosclerosis where ET-1 levels may be elevated. In such situations vasoconstriction of vasa vasorum by ET-1, via a direct effect and also by potentiating the contractile effects of other agonists, would theoretically promote such conditions since the nutrient supply to the host vessel wall would be impaired.

The vasa vasorum is also sensitive to several vasodilators. In vivo studies, again using microspheres, show that acetylcholine, histamine, isoprenaline, adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine or sodium nitroprusside all depress perfusion pressure through the vasa vasorum [16]. Additionally, precontracted isolated vasa relax to the vasodilators bradykinin (BK), SP and CGRP [6]. As in many other blood vessels relaxation to both SP and BK is endothelium-dependent. Endothelium-derived nitric oxide (NO) appears to mediate the responses to SP whilst the responses to BK may be more dependent on endothelium-dependent hyperpolarisation [6]. The high potency of these vasodilators in isolated vasa indicates that they may have an important role in controlling tone in the vasa vasorum. An increased sensitivity to vasodilators compared to vasoconstrictors would allow vasa to maintain a dilated state and thereby maintain blood flow to the vessel wall. Moreover, the finding that the endothelium is critical in mediating these responses may have significant implications in certain disease states or physical manoeuvers that result in damage to the endothelium.

Whilst it is clear that flow through the vasa vasorum may be regulated by vasoactive substances, the contribution of neurotransmitters on regulation of tone in vasa vasorum is not known. It is clear from immunohistochemical studies of isolated vessels that the vasa are innervated. Additionally, Heistad et al. demonstrated that blood flow through the vasa vasorum may be sensitive to neural stimulation since stimulation of the stellate ganglion of dogs decreased blood flow to the outer media of the thoracic aorta and stimulation of carotid sinus baroreceptors increased blood flow [28]. Therefore, in addition to certain humoral factors, the tone of vasa vasorum may also be regulated by neural influences. However there are no studies that have demonstrated neural responses in isolated vasa.


   3 Role of vasa vasorum in cardiovascular diseases
Top
 Abstract
 1 Morphology
 2 Regulation of blood...
 3 Role of vasa...
4 Conclusion
 References
 
The presence of the vasa vasorum in blood vessel walls is considered to be required for the maintenance of conduit vessel physiology. Evidence to support this hypothesis has been provided by experimental disruption of blood flow through the vasa vasorum of healthy blood vessels. Furthermore there is considerable evidence that the vasa vasorum may be involved in certain cardiovascular diseases, including atherosclerosis. The following section describes the potential significance of changes in vasa vasorum morphology and blood flow in specific cardiovascular diseases.

3.1 Atherosclerosis
Atherosclerosis is a progressive inflammatory disease of large arteries. The response to injury hypothesis proposes that endothelial dysfunction is the first step in development of atherosclerosis. However, it has recently been suggested that the vasa vasorum in the adventitia of large arteries have a crucial role in the pathogenesis of this disease. In 1966, Nakata and Shionoya [29] demonstrated that occlusion of blood flow through the vasa vasorum of canine abdominal aorta, with a thrombin and gelatin mix, results in an initial intimal thickening and smooth muscle proliferation with subsequent lipid deposition and hypertrophy of the neointima. In addition, studies on normal and atherosclerotic coronary arteries demonstrated an increase in microvessel density in atherosclerotic arteries that were derived from adventitial vasa vasorum, and lead to the hypothesis that neovascularisation of plaques has a role in the pathogenesis of atherosclerosis [30]. More recently, Martin et al. [31] described a model of atherosclerosis in rabbits, in which placement of an inert silastic collar around the outside of the carotid artery results in the formation of an atheroma-like intimal lesion. The authors argue that occlusion of the adventitial vasa vasorum by the collar leads to hypoxia of the vessel wall and that this initiates smooth muscle cell proliferation and migration. However, the mechanisms of collar-induced lesions are controversial. Intimal thickening was also observed in the rabbit thyroid artery, a small branch of the carotid artery, despite the absence of vasa vasorum in these arteries [32]. Nevertheless, Barker et al. [33] demonstrated that removal of the adventitia containing the vasa vasorum of carotid arteries from rabbits, induces an intimal lesion supporting the hypothesis that disruption of vasa vasorum blood flow initiates vascular lesions. Furthermore ligation of the side branches of femoral arteries, and hence disruption of vasa vasorum blood flow, in the Yucatan miniature pig produces significant intimal hyperplasia [34]. Similarly, removal of the periaortic fat containing the vasa vasorum of canine ascending aorta results in extensive medial necrosis and an acute decrease in aortic distensibility [35]. Collectively these studies suggest that impairment of nutrient blood flow through the vasa vasorum may contribute to vessel wall hypoxia and that they might allow predisposition to atherosclerosis or other degenerative conditions of the host vessel. All of these studies, however, used artificial means to reduce flow through vasa vasorum. The fact that vasa vasorum regulate their own tone identifies a possible mechanism whereby flow through the vasa may be disrupted. Atherosclerosis is associated with elevation of ET-1 levels [36] and it is conceivable that arterial vasa might constrict in response to this ET-1 thus reducing nutrient blood flow to the vessel wall.

The number of vasa vasorum supplying large arteries remains constant throughout life. However, vasa can proliferate in response to acute arterial injury. In particular, studies on the vasa vasorum of coronary arteries from hypercholesterolemic pigs suggest that the three-dimensional pattern of second order vasa increases and becomes disorganised [5]. As mentioned above, the vasa vasorum are sensitive to oxygen tension and therefore the proliferation of vasa vasorum in arteries occluded by atheromatous plaques may be due to decreased oxygen tension in the vessel wall. The severity of atherosclerosis is directly related to the density of adventitial vasa [15] but the role of newly formed microvessels in the chronic processes of atherogenesis is unknown. There are currently two postulates [37]; firstly, microvessels that grow into the media and intima may nourish and stabilise the growing plaque by delivering growth factors and hormones. Support for this hypothesis is provided by immunohistochemical and confocal microscopy studies on microvessels in human coronary arteries [38]. These studies demonstrated the presence of microvessels in thickened intimas and atherosclerotic plaques that was directly related to the size of the plaque and inversely related to lumen diameter. This rich neovascularisation could be traced from adventitial vasa vasorum through the media and occurred predominantly at the base of the plaque at the border with the normal intima. Albumin and fibrinogen leakage was associated with these microvessels and immunoglobulin containing cells were observed surrounding microvessels indicating that intimal vascularisation contributes to nourishment of atheromatous plaques and inflammation in conduit blood vessel walls. Unlike the resident vasa, it has been suggested that these newly developed vasa are typically fragile endothelial channels without smooth muscle layers [39] and therefore do not have the capacity to regulate tone. In contrast, a study by Williams et al. in monkeys demonstrates vasa in the intima-media of coronary arteries with a single layer of smooth muscle, suggesting that these vessels may have some capacity to regulate tone [15]. This study also suggests that the smooth muscle of vasa vasorum of atherosclerotic arteries is more sensitive to vasoconstrictors, possibly due to the enhancing actions of local endothelins. A decrease in blood flow to the vessel wall would contribute to further vessel wall hypoxia and presumably thereby aid the progression of atheroma formation.

It has also been suggested that these vasa may limit the progression of the lesion by maintaining nutrient blood flow to the thickened vessel wall. Indeed studies using the microsphere technique in coronary arteries of monkeys demonstrated a substantial increase in blood flow through the vasa vasorum of arteries of atherosclerotic animals [15]. Furthermore, Barker et al [33] demonstrated that intimal lesions in rabbit carotid arteries can regress on the formation of a ‘neoadventitia’, suggesting that maintenance of blood flow through the vasa vasorum might limit neointimal formation.

Therefore, there is a paradox regarding the benefit of proliferation of vasa vasorum in atherosclerosis. Whilst these vessels provide a significant increase in nutrient blood flow to the thickened artery wall, several studies suggest that these vessels are ‘leaky’ and prone to rupture. These vessels may thereby contribute to intraplaque haemorrhage, plaque rupture and formation of thrombi. In addition if, in some cases, these vessels do contain smooth muscle, they appear to be more sensitive to constrictors and therefore blood flow through these particular vessels may be compromised.

3.2 Restenosis
Transluminal angioplasty is now a common method of restoring blood flow in vessels that are occluded with atheromatous plaques. However, within 6 months, vessel size often returns to preangioplasty dimensions (restenosis). Recently, a three-dimensional study of the anatomy of normal and balloon-injured porcine coronary arteries has demonstrated that there is a decrease in the ratio of first order to second order vasa 28 days after balloon injury. Furthermore, the density of vasa was directly related to the severity of stenosis [40]. However, it is not yet clear whether these changes in the vasa vasorum are a consequence or a cause of changes in the vessel wall.

Balloon angioplasty is associated with stretching and splitting of the intima/media as well as the adventitia of the vessel [41]. Additionally, several studies clearly show endothelial damage of the large vessel following this procedure. Of interest is the possibility that these procedures may also damage the endothelium of the vasa vasorum resulting in impaired endothelium-dependent control of blood flow to the vessel wall and subsequent vessel wall hypoxia. Hypoxia itself is a stimulus for the induction of several growth factors and cytokines and in this way may contribute to the mechanisms of luminal narrowing. Several authors have investigated the effect of angioplasty on the morphology and blood flow through the vasa vasorum but the findings are inconclusive. In 1982, Train et al. observed a fine vascular network around the femoral arteries of three patients immediately following angioplasty that may have represented hypertrophied vasa [42]. Yet Cragg et al. did not observe any acute (up to 7 days postangioplasty) morphological changes in the vasa vasorum of dilated canine carotid arteries [43]. In contrast, studies on the long-term effects of angioplasty in dogs showed considerable stretching and rupture of the vasa vasorum that was followed by extensive proliferation of vasa [44]. However, this increased vascularisation following angioplasty completely regresses by 18 months [45]. The functional effects of these morphological changes in the vasa vasorum are not known; measurements of vasa vasorum blood flow, using the microsphere technique in dogs, showed that blood flow may be increased [43] or decreased [46] immediately after angioplasty. Furthermore, in a balloon-injury model in the rat carotid artery it has been shown that there is an initial decrease in neuronal CGRP and SP-immunoreactivity around the vasa vasorum of the injured vessel and a compensatory increase in the control contralateral vessel [9]. It is clear that CGRP and SP may normally vasodilate vasa vasorum [6] and therefore a decrease in the supply of these peptides would presumably decrease vasa vasorum blood flow to the host vessel wall.

3.3 Hypertension
Power-Doppler imaging of blood flow through the vasa vasorum of normal human carotid arteries demonstrate that perfusion of vasa vasorum occurs after the main flow velocity in the lumen of the carotid artery [47]. This suggests that, similar to the coronary circulation, the vasa vasorum fill during diastole. It may therefore be expected that an increase in arterial pressure in the host vessel leads to a reduction in perfusion of the vasa vasorum. In order to test this hypothesis Sacks used a model of a section of the aortic wall, comprising a simulated vasa embedded in a block of soft material, and measured the patency of the vasa (flow per unit pressure drop) [48]. In this model, elevation of radial stress on the vasa resulted in decreased patency of vasa vasorum. The author suggests that elevation of blood pressure and thus compression of the aortic wall reduces blood flow through the vasa vasorum. Furthermore, measurements of blood flow in canine thoracic aortic wall, using the microsphere technique, indicate a substantial reduction in the vasodilator capacity of vasa vasorum in animals with chronic hypertension [49]. Therefore it is possible that associated increases in wall tension in hypertension distort the vasa vasorum thus leading to underperfusion and changes in blood vessel walls. Indeed previous studies in canine aorta indicate that disruption of vasa vasorum flow produces acute changes in distensibility and structural changes of the aortic wall [35]. Studies using isolated vasa vasorum indicate that under normal conditions these vessels are insensitive to NA and AngII. However, it is clear that the contractile reactivity of these vessels may be dramatically altered under certain conditions [21] and therefore this insensitivity to vasoconstrictors is not due to the lack of expression of receptors. Therefore, in a situation such as hypertension, it is conceivable that increases in sensitivity to constrictors may occur. Such decreases in vasa vasorum blood flow would compound the situation by producing vessel wall hypoxia, a stimulus for remodelling.

3.4 Deep vein thrombosis and vein bypasses
The vasa venarum is likely to be the most important source of nutrition for the walls of large veins. O’Neill [4] demonstrated that experimental disruption of the vasa venarum of canine jugular vein results in an increase in permeability of endothelial cells. Subsequent accumulation of fluid beneath the endothelial layer caused the endothelial cells to lift off. It is apparent that damage to endothelial cells is the precursor for thrombus formation. Therefore, disruption of blood flow through microvessels supplying large veins may have a role in endothelial damage and subsequent thrombosis.

Similarly, one may speculate that disruption of vasa venarum blood flow during venous bypasses has implications on the viability of the bypass. Vasa are sensitive to oxygen tension and therefore exposure of vasa venarum to arterial oxygen tension may also alter the number and distribution of these vessels. However, despite acute changes in distribution of vasa venarum [50], there is little evidence that indicates that these changes affect the health of the grafted vein. For example, a study of vein bypasses in dogs demonstrated that these procedures do not affect the integrity of the endothelium of the arterialised vein [51].


   4 Conclusion
Top
 Abstract
 1 Morphology
 2 Regulation of blood...
 3 Role of vasa...
 4 Conclusion
References
 
Despite an increase in attention to the vasa vasorum relatively little is known about the regulation of blood flow through these microvessels. Recent studies on isolated vasa suggest that tone may be regulated by several vasoactive substances including endothelium and neuronally-derived agents. However, the profile of reactivity of the vasa vasorum appears to be different to other resistance arteries of a similar diameter, a possible reflection of their function. Studies with endothelin suggest that this mediator may be of particular importance in determining the contractile state and reactivity of the vasa vasorum. Therefore, endothelin receptor antagonists may be useful in preserving or restoring nutrient blood flow to conduit blood vessel walls. Disruption of the vasa vasorum of healthy blood vessels results in vascular lesions and certain vascular diseases are associated with changes in the vasa vasorum, which are directly related to the severity of the disease. It is clear that these vessels are not passive bystanders and a greater understanding of their biology is likely to give insight into processes of vascular disease and identify novel targets for drug action.

Time for primary review 24 days.


   Acknowledgements
 
We would like to thank Professor J.M. Polak and Dr. L.D.K Buttery for their technical advice and Dr. R. Corder for his kind tift of antibody to NPY. AA is the recipient of an intermediate BHF Fellowship and RS is funded by an MRC studentship.


   References
Top
 Abstract
 1 Morphology
 2 Regulation of blood...
 3 Role of vasa...
 4 Conclusion
 References
 

  1. Woerner C.A. The arterial wall. (1959) Baltimore: Williams and Wilkins. 1–14.
  2. Lowenberg RI, Shumacker HB. Morphologic observations of normal vasa vasorum. Yale J Biol Med 1940;395–401.
  3. Brook W.H. Vasa vasorum of veins in dog and man. Angiology (1977) 28:351–360.[Free Full Text]
  4. O’Neill J.F. The effects on venous endothelium of alterations in blood flow through the vessels in the vein walls and the possible relation to thrombosis. Ann Surg (1947) 126:270–288.[Web of Science][Medline]
  5. Kwon H.M., Sangiorgi G., Ritman E.L., et al. Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Clin Invest (1998) 101:1551–1556.[Web of Science][Medline]
  6. Scotland R.S., Vallance P., Ahluwalia A. On the regulation of tone in vasa vasorum. Cardiovasc Res (1999) 41:237–245.[Abstract/Free Full Text]
  7. Herbst W.M., Eberle K.P., Ozen Y., Hornstein O.P. The innervation of the great saphenous vein: an immunohistochemical study with special regard to regulatory peptides. Vasa (1992) 21:253–257.[Web of Science][Medline]
  8. Crowe R., Burnstock G., Dickinson I.K., Pryor J.P. The human penis: an unusual penetration of NPY-immunoreactive nerves within the medial muscle coat of the deep dorsal vein. J Urol (1991) 145:1292–1296.[Web of Science][Medline]
  9. Milner P., Crowe R., Loesch A., Anglin S., Burnstock G., McEwan J.R. Neurocompensatory responses to balloon-catheter-induced injury of rat carotid artery. J Vasc Res (1997) 34:31–40.[Web of Science][Medline]
  10. Geiringer E. Intimal vascularization and atherosclerosis. J Pathol Bacteriol (1951) 63:201–211.[CrossRef][Web of Science][Medline]
  11. Wolinsky H., Glagov S. Nature of species differences in the medial distribution of aortic vasa vasorum in mammals. Circ Res (1967) 20:409–421.[Abstract/Free Full Text]
  12. Heistad D.D., Armstrong M.L., Amundsen S. Blood flow through vasa vasorum in arteries and veins: effects of luminal pO2. Am J Physiol (1986) 250:H434–H442.[Web of Science][Medline]
  13. Sobin S., Frasher W.G., Tremer H.M. Vasa vasorum of the pulmonary artery of the rabbit. Circ Res (1962) 11:257–263.[Abstract/Free Full Text]
  14. Heistad D.D., Marcus M.L., Law E.G., Armstrong M.L., Ehrhardt J.C., Abboud F.M. Regulation of blood flow to the aortic media in dogs. J Clin Invest (1978) 62:133–140.[Web of Science][Medline]
  15. Williams J.K., Armstrong M.L., Heistad D.D. Vasa vasorum in atherosclerotic coronary arteries: responses to vasoactive stimuli and regression of atherosclerosis. Circ Res (1988) 62:515–523.[Abstract/Free Full Text]
  16. Ohhira A., Ohhashi T. Effects of aortic pressure and vasoactive agents on the vascular resistance of the vasa vasorum in canine isolated thoracic aorta. J Physiol (1992) 453:233–245.[Abstract/Free Full Text]
  17. Dahm P.L., Bodelsson M., Tornebrandt K., et al. Binding of [3H]-5-hydroxytryptamine to human coronary artery and bypass graft vessels. Cardiovasc Res (1996) 31:800–806.[Abstract/Free Full Text]
  18. Awane-Igata Y., Ikeda S., Watanabe T. Inhibitory effects of TAK-044 on endothelin induced vasoconstriction in various canine arteries and porcine coronary arteries: a comparison with selective ETA and ETB receptor antagonists. Br J Pharmacol (1997) 120:516–522.[CrossRef][Web of Science][Medline]
  19. Pierre L.N., Davenport A.P. Endothelin receptor subtypes and their functional relevance in human small coronary arteries. Br J Pharmacol (1998) 124:499–506.[CrossRef][Web of Science][Medline]
  20. Haynes W.G., Webb D.J. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet (1994) 344:852–854.[CrossRef][Web of Science][Medline]
  21. Scotland R.S., Vallance P.J.T., Ahluwalia A. Endothelin alters the reactivity of vasa vasorum: mechanisms and implications for conduit vessel physiology and pathophysiology. Br J Pharmacol (1999) 128:1229–1234.[CrossRef][Web of Science][Medline]
  22. Okatani Y., Taniguchi K., Sagara Y. Amplifying effect of endothelin-1 on serotonin-induced vasoconstriction of human umbilical artery. Am J Obstet Gynecol (1995) 172:1240–1245.[CrossRef][Web of Science][Medline]
  23. Yang Z.H., Richard V., von Segesser L., et al. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm? Circulation (1990) 82:188–195.[Abstract/Free Full Text]
  24. Tabuchi Y., Shi S-J., Mikami H., Ogihara T. Endothelin modulates L-N-nitroarginine-induced enhancement of vasoconstriction evoked by norepinephrine. J Cardiovasc Pharm (1991) 17:S203–S205.[Web of Science][Medline]
  25. Tabuchi Y., Nakamaru M., Rakugi H., Nagano M., Ogihara T. Endothelin enhances adrenergic vasoconstriction in prefused rat mesenteric arteries. Biochem Biophys Res Comm (1989) 159:1304–1308.[CrossRef][Web of Science][Medline]
  26. Zhang J-X., Okamura T., Toda N. Pre- and postjunctional modulation by endothelin-1 of the adrenergic neurogenic response in canine mesenteric arteries. Eur J Pharmacol (1996) 311:169–176.[CrossRef][Web of Science][Medline]
  27. Lerman A., Webster M.W., Chesebro J.H., et al. Circulating and tissue endothelin immunoreactivity in hypercholesterolemic pigs. Circulation (1993) 88:2923–2928.[Abstract/Free Full Text]
  28. Heistad D.D., Marcus M.L., Martins J.B. Effects of neural stimuli on blood flow through vasa vasorum in dogs. Circ Res (1979) 45:615–620.[Abstract/Free Full Text]
  29. Nakata Y., Shionoya S. Vascular lesions due to obstruction of the vasa vasorum. Nature (1966) 212:1258–1259.[CrossRef][Web of Science]
  30. Barger A.C., Beeuwkes I.I.I.R., Lainley L.L., et al. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. New Eng J Med (1984) 310:175–177.[Web of Science][Medline]
  31. Martin J.F., Booth R.F.G., Moncada S. Arterial wall hypoxia following thrombosis of the vasa vasorum is an initial lesion in atherosclerosis. Eur J Clin Invest (1991) 21:355–359.[Web of Science][Medline]
  32. De Mayer G.R.Y., Van Put D.J.M., Kockx M.M., et al. Possible mechanisms of collar-induced intimal thickening. Arterioscler Thromb Vasc Biol (1997) 17:1924–1930.[Abstract/Free Full Text]
  33. Barker S.G.E., Tilling L.C., Miller G.C., et al. The adventitia and atherogenesis:removal initiates intimal proliferation in the rabbit which regresses on generation of a ‘neoadventitia’. Atherosclerosis (1994) 105:131–144.[CrossRef][Web of Science][Medline]
  34. Barker S.G.E., Talbert A., Cottam S., Baskerville P.A., Martin J.F. Arterial intimal hyperplasia after occlusion of the adventitial vasa vasorum in the pig. Arterioscler Thromb Vasc Biol (1993) 13:70–77.[Abstract/Free Full Text]
  35. Stefanadis C.I., Karayannacos P.E., Boudouas H.K., et al. Medial necrosis and acute alterations in aortic distensibility following removal of the vasa vasorum of canine ascending aorta. Cardiovasc Res (1993) 27:951–956.[Abstract/Free Full Text]
  36. Bacon C.R., Cary N.R., Davenport A.P. Endothelin peptide and receptors in human atherosclerotic coronary artery and aorta. Circ Res (1996) 79:794–801.[Abstract/Free Full Text]
  37. Pels K., Labinaz M., O’Brien E.R. Arterial wall neovascularization — potential role in atherosclerosis and restenosis. Jpn Circ J (1997) 61:893–904.[CrossRef][Medline]
  38. Zhang Y., Cliff W.J., Schoefl G.I., et al. Immunohistochemical study of intimal microvessels in coronary atherosclerosis. Am J Pathol (1993) 143:164–172.[Abstract]
  39. Williams J.K., Armstrong M.L., Heistad D.D. Blood flow through new microvessels: factors that affect regrowth of vasa vasorum. Am J Physiol (1988) 254:H126–H132.[Web of Science][Medline]
  40. Kwon H.M., Sangiorgi G., Ritman E.L., et al. Adventitial vasa vasorum in balloon-injured coronary arteries: visualization and quantitation by a microscopic three-dimensional computed tomography technique. J Am Coll Cardiol (1998) 32:2072–2079.[Abstract/Free Full Text]
  41. Scott N.A., Cipolla G.D., Ross C.E., et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation (1996) 93:2178–2187.[Abstract/Free Full Text]
  42. Train J.S., Mitty H.A., Efremidis S.C., Rabinowitz J.G. Visualization of a fine periluminal vascular network following transluminal angioplasty: possible demonstration of the vasa vasorum. Radiology (1982) 143:399–403.[Free Full Text]
  43. Cragg A.H., Einzig S., Rysavy J.A., Castaneda-Zuniga W.R., Borgwardt B., Amplatz K. The vasa vasorum and angioplasty. Radiology (1983) 148:75–80.[Abstract/Free Full Text]
  44. Zollikofer C.L., Redha F.H., Bruhlmann W.F., et al. Acute and long-term effects of massive balloon dilation on the aortic wall and vasa vasorum. Radiology (1987) 164:145–149.[Abstract/Free Full Text]
  45. Pisco J.M., Correia M., Esperanca-Pina J.A., de Sousa L.A. Changes in the vasa vasorum following percutaneous transluminal angioplasty in a canine model of aortic stenosis. J Vasc Intervent Radiol (1994) 5:561–566.[Web of Science][Medline]
  46. Eisenhauer A.C., Alker K., Kloner R., Matthews R.V. The effect of balloon angioplasty on vasa vasorum blood flow in canine coronary arteries. Am Heart J (1990) 120:1285–1291.[CrossRef][Web of Science][Medline]
  47. Belcaro G., Laurora G., Cesarone M.R., et al. Vasa vasorum visualised by Power-Doppler in normal and arteriosclerotic carotid arteries. Vasa (1996) 25:226–232.[Web of Science][Medline]
  48. Sacks A.H. The vasa vasorum as a link between hypertension and arteriosclerosis. Angiology (1975) 26:385–390.[Free Full Text]
  49. Marcus M.L., Heistad D.D., Armstrong M.L., et al. Effects of chronic hypertension on vasa vasorum in the thoracic aorta. Cardiovasc Res (1985) 19:777–781.[Abstract/Free Full Text]
  50. Boerboom L.E., Olinger G.N., Liu T.Z., Rodriguez E.R., Ferrans V.J., Kissebah A.H. Histologic, morphometric, and biochemical evolution of vein bypass grafts in a nonhuman primate model. I. Sequential changes within the first three months. J Thorac Cardiovasc Surg (1990) 99:97–106.[Abstract]
  51. Corson J.D., Leather R.P., Balko A., Naraynsingh V., Karmody A.M., Shah D.M. Relationship between vasa vasorum and blood flow to vein bypass endothelial morphology. Arch Surg (1985) 120:386–388.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Scotland, R. S.
Right arrow Articles by Ahluwalia, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scotland, R. S.
Right arrow Articles by Ahluwalia, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?