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Cardiovascular Research 1999 42(3):600-606; doi:10.1016/S0008-6363(99)00020-6
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Copyright © 1999, European Society of Cardiology

Spotlight on microcirculation: an update

Isabella Tritto and Giuseppe Ambrosio*

Division of Cardiology, Department of Clinical and Experimental Medicine, University of Perugia, Via Eugubina 42, 06122 Perugia, Italy

cardiopg{at}unipg.it

* Corresponding author. Tel.: +39-75-585-5842; fax: +39-75-585-5840

Received 8 July 1998; accepted 15 January 1999


   1 Introduction
Top
 1 Introduction
2 Microcirculation as the...
 3 Biophysical mechanisms of...
 4 New mediators of...
 5 Microcirculation during...
 6 Microvascular alterations in...
 7 Microcirculation and...
 References
 
Over the past 3 decades there has been an increasing interest in the better understanding of the role of microcirculation under a variety of conditions. Therefore, in 1996 Cardiovascular Research devoted the whole October issue to microcirculation. Two years later the interest in this field is far from being reduced, as the number of articles published has remained high, with over 800 papers per year. The purpose of this article is to review several major studies which have appeared over the last 2 years in this field, which update the various key areas of research that were extensively reviewed in the 1996 issue.


   2 Microcirculation as the site of exchange of gases and metabolites
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 1 Introduction
 2 Microcirculation as the...
3 Biophysical mechanisms of...
 4 New mediators of...
 5 Microcirculation during...
 6 Microvascular alterations in...
 7 Microcirculation and...
 References
 
Oxygen delivery to tissue has long been considered to take place almost exclusively at the capillary level. However, it has progressively become appreciated that tissue oxygenation is the result of a complex process in which a substantial amount of oxygen is exchanged through arterioles, which in some tissues may be a greater oxygen source than capillaries (see review article by Intaglietta et al. [1]). Very recently, gas diffusion in postcapillary venules has also been supposed to occur, and it has been hypothesized that gas diffusive transfer may play an important role in regulating tissue oxygenation. Given the parallel arrangement of small arteries and veins in several tissues, oxygen transfer from arterial to venous vessels may result in diffusion shunting of oxygen, which may be detrimental to tissue oxygenation; on the other hand, diffusive transfer from arterioles to capillaries and among capillaries might contribute to homogeneous tissue oxygenation. Diffusion of CO2 might also improve tissue oxygenation, since CO2 diffusion from venules to arterioles would reduce pH in arterial blood and thus increase O2 release from hemoglobin. In this regard, it has recently been shown that in rat skeletal muscle diffusion shunting of oxygen from arterioles to postcapillary venules is enhanced during hyperoxia, while during hypoxia CO2 accumulates in peripheral vessels [2].

Thus, diffusive shunting of oxygen and counter diffusion and accumulation of CO2 may represent an important mechanism contributing to the homeostasis of tissue oxygenation levels [2]. Analysis of the spatial distribution of PO2 in venular structures has indicated that longitudinal O2 gradients and spatial heterogeneity are only weakly dependent on mean systemic blood pressure, further supporting the hypothesis that venules may play an important role in regulating oxygen delivery [3]. A recent study in dog intestine has shown that an increase in the vasoconstricting tone causes a redistribution of flow towards mucosa, both under high and low flow conditions, which correlates with the improvement in oxygen extraction ratio [4]. Interestingly, capillary transit time heterogeneity remained unchanged, suggesting that this variable is tightly regulated in the intestine.

The long-standing controversy over the determinants of macromolecule transport through the endothelium of microvessels was discussed by Michiel [5]. In addition to convective transport through pores in endothelial cells, at least four different mechanisms of vesicular transport across endothelium have been hypothesized. Evidence available does not allow to clearly eliminate any of them, and it is likely that no single mechanism can account for transport of all macromolecules in all endothelia [5]. Recent evidence in the eel swim bladder has shown that transcytosis of insulin and albumin occurs via different sets of plasmalemmal vesicles, probably through receptor-mediated mechanisms [6].

Much work has focused on the mechanisms of the increase in vascular permeability induced by vascular endothelial growth factor (VEGF), an endothelial cell mitogen that plays a major role in angiogenesis. Angiogenesis is preceded by enhanced microvascular permeability, that is mediated by the interaction of VEGF with the R2 receptor subtype, and implicates nitric oxide and prostacyclin production [7].


   3 Biophysical mechanisms of flow regulation in microcirculation
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 1 Introduction
 2 Microcirculation as the...
 3 Biophysical mechanisms of...
4 New mediators of...
 5 Microcirculation during...
 6 Microvascular alterations in...
 7 Microcirculation and...
 References
 
Vessel arrangements and biophysical behavior of blood components within the vasculature are of major importance in regulating the transport and exchange function of microvessels (see review by Pries et al. [8]). Changes in rheological properties of the erythrocytes affect resistance to flow; this phenomenon is partly mediated by changes in the thickness of the marginal cell-free layer in microvessels (≤40 µm). This phenomenon has been studied both in vivo and in artificial models of circulation, although it has now become appreciated that microvascular resistance to flow in vivo is higher than in glass tubes of similar diameters [8]. In addition, since microvessels are arranged as a network, vascular function is strongly influenced by vessel architecture. Recent studies have shown that reduced elasticity of microvessel walls can significantly alter the adaptive response to changes in rheological properties, resulting in increased resistance to flow [9]. Analysis of red cell motion through cylindrical micropores has shown that filterability of erythrocytes is dependent on their resistance to transient deformations [10]. Although increased red cell resistance to deformation may impair microcirculation at low temperatures, this phenomenon is not likely to result in significant worsening of flow reduction in vivo, with effects comparable to those resulting from changes in plasma and blood viscosity [11].

The various mechanisms that induce vasodilation in the coronary bed act coordinately and in an integrated fashion to regulate blood flow, with complex interactions [12]. Microvessels of different diameters exhibit different sensitivity to vasoactive stimuli, with a longitudinal gradient in vasoactive responses; for example, response to metabolic vasodilation mainly involves small arterioles (≤40 µm). However, vasodilation of a segment of the microvascular tree affects pressure and flow in both proximal and distal vascular beds, thus eliciting myogenic and shear-stress dependent responses that make an important contribution to the final net effect on vascular resistance and flow. This concept has found further support in a study by Liao and Kuo who, using a modeling approach have shown that about 20% of the adenosine-induced increase in flow is actually dependent upon shear-sensitive mechanisms [13]. In fact, dilation of small arteries in response to adenosine increases flow in spite of decreasing pressure; increased flow in turn activates the shear-sensitive mechanism in up-stream arterioles, further enhancing flow [13]. The complexity of flow regulation is also depicted in a study by Komaru et al., showing that, while activation of G-proteins results in dilation of both large (>130 µm) and small (<130 µm) microvessels, the mechanisms underlying these effects are different and vessel size dependent. In small vessels vasodilation is mediated by activation of ATP-sensitive K+ channels, while in large microvessels it is induced through activation of the nitric oxide pathway and ATP-sensitive K+ channels in a synergistic fashion [14]. These observations further confirm the complexity and intricate regulation of flow in coronary microcirculation.


   4 New mediators of microvascular regulation
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 1 Introduction
 2 Microcirculation as the...
 3 Biophysical mechanisms of...
 4 New mediators of...
5 Microcirculation during...
 6 Microvascular alterations in...
 7 Microcirculation and...
 References
 
It has recently been appreciated that, in addition to nitric oxide, another gaseous molecule, carbon monoxide, may serve as mediator of vascular cell relaxation, by activating soluble guanylate cyclase to produce cGMP [15]. Carbon monoxide is generated by two forms of heme oxygenase, an inducible enzyme (HO-1), and a constitutive enzyme (HO-2). In the liver, HO-1 has been found in Kupfer cells only, while the constitutive form is present in parenchymal cells, and constitutive release of carbon monoxide by HO-2 appears to play a major role in regulation of microvascular tone, since administration of carbon monoxide-trapping agents results in marked sinusoidal constriction [16]. Interestingly, expression of HO-1 in liver can be stimulated by nitric oxide donors, which induce a progressive increase of HO-1 mRNA and protein activity [17].

An increasing number of observations suggests a role for carbon monoxide as a signalling molecule, in liver and in other organs. Release of carbon monoxide appears to play a major role also in the hemodynamic alterations of endo-toxic shock. In the postischemic heart, increased mRNA levels of heme oxygenase have been reported [18], and it has been suggested that myocardial preservation by nitric oxide may be modulated, at least in part, by carbon monoxide signaling [18]. Both forms of heme oxygenase are expressed in brain [19], where endogenous carbon monoxide is involved in the control of oxytocin release [20]. Finally, induction of HO-1 is also involved in nitric oxide-stimulated keratinocyte proliferation [21]. Taken together, these studies suggest that carbon monoxide might play an important role as a messenger molecule in a number of pathophysiological conditions.

The role of pericytes in vessel architecture has also received increasing attention. Pericytes have different morphology and distribution in various tissues, suggesting differences in function [22]. They express contractile protein and may contract, changing capillary resistance to flow, and it has been suggested that pericytes may further differentiate into smooth muscle cells. Communication between pericytes and endothelium involves release of soluble mediators and direct interaction via membrane proteins. Pericytes are now considered important modulators of physiological events like changes in capillary resistance and angiogenesis, and they have also been involved in pathological conditions like hypertension, diabetes and tumor vascularization. The enzyme aminopeptidase A, which is associated with microvessels of all organs in animals, has been found on cell membranes of activated pericytes in conditions associated with neovascularization, while it is present at very low concentrations in normal vessels [23]. This observation supports a regulatory role for pericytes during neovascularization, and may represent a marker of pericytes activation. Evidence supporting a role for pericytes in diabetic retinopathy is discussed below.


   5 Microcirculation during inflammation
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 1 Introduction
 2 Microcirculation as the...
 3 Biophysical mechanisms of...
 4 New mediators of...
 5 Microcirculation during...
6 Microvascular alterations in...
 7 Microcirculation and...
 References
 
In the heart postischemic reperfusion is accompanied by an inflammatory reaction, with release of proinflammatory and fibrogenic mediators that promote tissue healing; however, this phenomenon may also result in leukocyte-mediated cardiac injury [24–26]. In fact, activated neutrophils may infiltrate postischemic myocardium through sequential steps of rolling along vessel walls, adhesion to endothelium and migration in tissues, where they release cytotoxic mediators with subsequent myocardial injury [27]. Since reperfusion is accompanied by a decrease in venular shear forces, and by an increase in neutrophil rolling, adhesion and extravasation, it has been suggested that conditions of slow flow may contribute to neutrophil recruitment in tissues. In postischemic mesenteric microvasculature, maintaining shear forces at control values did not affect the number of rolling leukocytes, but it did reduce the number of adherent cells and subsequent microvascular dysfunction [28]. This observation suggests that decreased shear stress does not contribute to initial neutrophil activation, but it is an essential permissive component for neutrophil firm adhesion and extravasation in postischemic microvasculature [28]. Also, in postischemic hearts low-flow reperfusion further increases neutrophil accumulation in coronary microcirculation [29]. These findings may have important clinical implications, since neutrophil accumulation in postcapillary vessels is the major determinant to the no-reflow phenomenon [30]. Clinical studies indicate that the no-reflow phenomenon does occur in man [31]. The occurrence of no-reflow has major prognostic implications, since it is associated with worse contractile recovery, higher incidence of arrhythmias and pericardial effusion, and with late development of left ventricular dilatation and congestive heart failure [31]. Interestingly, no-reflow mostly occurred in all patients with slow flow in the epicardial artery after percutaneous transluminal coronary angioplasty, while it was only present in a minority of patients with almost normal flow in the epicardial artery [32]. These clinical findings might be explained by recent data of Kubes [28] and Ritter and McDonogh [29], which indicate that neutrophil accumulation in postischemic tissues is greatly enhanced under conditions of slow flow.

Mast cells may release several proinflammatory mediators, and their activation has been proposed to play a major role in a variety of pathophysiological situations by promoting leukocyte recruitment and inflammation [33]. Mast cell activation has also been involved in the inflammatory reaction that occurs during postischemic reperfusion in the heart [27,34]. Monocytes have also been shown to play an important role in tissue healing, and their recruitment is mediated by different factors. Release of the complement factor C5a is the major product of monocyte chemotaxis in the first hour after reperfusion, while transforming growth factor 1 (TGF-β 1) is released between 60 and 180 min; after 180 min TGF-β 1 and monocyte chemoattractant protein-1 coordinately promote monocyte recruitment [35]. Exposure to oxidized LDL also induces mast cell activation and leukocyte–endothelial cell adhesion [36], events that have been proposed as initial steps in the development of atherosclerotic plaque. Mast cell stabilization attenuated leukocyte–endothelial cell adhesion in response to oxidized LDL, indicating that these cells are involved in the microvascular dysfunction induced by oxidized LDL [36].

Other studies have investigated the mechanisms of neutrophil adhesion to the endothelium. The ability of leukocytes to cross the vessel wall is fundamental, since it allows these cells to reach the site of tissue inflammation where they may exert their actions, and firm adherence to endothelium is the first step of this process [37]. Exposure of CD11 integrins on neutrophil surface plays an important role in this phenomenon, and it has been appreciated that specific integrins may have different roles in cell adhesion. CD11b integrin plays a critical role in mediating binding of neutrophils to fibrinogen and neutrophil degranulation, but it is not necessary for effective neutrophil emigration, which is more dependent upon CD11a [38]. To evaluate the role of P-selectin and ICAM-1 in mediating leukocyte rolling, genetically engineered mice lacking one or both these adhesion molecules have been subjected to trauma- and cytokine-induced inflammation [39]. In normal mice, leukocyte rolling is largely mediated by P-selectin, and in part by ICAM-1. In mice lacking both molecules, leukocyte rolling during inflammation still occurred to some extent, and it was abolished by antibodies directed against E-selectin, clearly demonstrating E-selectin dependent rolling in vivo [39]. Interestingly, leukocyte rolling induced by Tumor Necrosis Factor {alpha} is increased by blockade of endogenous nitric oxide production, while it is not affected by exogenous nitric oxide donors [40]. This seems to be a specific phenomenon, since inhibition of nitric oxide synthase did not affect leukocyte recruitment during ischemia–reperfusion [40]. Thus, increased production of nitric oxide seems to play an important role in dampening leukocyte recruitment in response to pro-inflammatory cytokines, while during postischemic reperfusion other mechanisms probably overcome this regulation. It has also been demonstrated that neutrophil migration across Interleukin-1 stimulated cultured endothelium occurs preferentially where the borders of three endothelial cells intersect, independently of tight junctions [41].

Postischemic reperfusion is accompanied by profound endothelial dysfunction, mediated by oxygen radical generation and inhibition of nitric oxide synthase activity [25,42,43]. Reduced nitric oxide production results in upregulation of cell adhesion molecules that in turn stimulates neutrophil recruitment and myocardial injury during reperfusion [25,42,43]. This phenomenon has now been reported in the lung, in which inhaled nitric oxide attenuated the microvascular leak induced by ischemia–reperfusion [44]. However, conflicting data have been obtained by Huang et al. Inhibition of nitric oxide synthase worsened lung injury when ischemia was performed during normoxic ventilation, while it attenuated lung injury during hypoxic ischemia [45]. Very interesting data have been published by Lefer et al. [46,47] who showed that low concentrations of peroxynitrite, a powerful oxidant formed in the reaction of nitric oxide with superoxide radicals, inhibits leukocyte–endothelial cell interactions [46]. Administration of nanomolar concentrations of peroxynitrite to postischemic hearts attenuated contractile dysfunction, and reduced neutrophil infiltration and infarct size [46,47].

Endotoxemia induces a microvascular inflammatory response that results in endothelial activation, with induction of a procoagulant state, increased adhesiveness of leukocytes and platelets to the vessel wall, and loss of arteriolar tone. Reduced organ perfusion and release of toxic mediators by activated endothelium and blood cells result in tissue damage [48]. In addition to the large number of mediators that have been already involved in the pathophysiology of this phenomenon, release of carbon monoxide has recently been suggested to play a major role in the hemodynamic alterations of endotoxic shock [49]. HO-1 expression is stimulated in rat arteries during endotoxic shock, with an 8-fold increase in enzyme activity in vascular smooth muscle cells, and inhibition of HO-1 induction also abolishes endotoxin-induced hypotension [49]. Interestingly, HO-1 induction in vessel walls during endotoxin shock seems to be independent of nitric oxide production [49]. Endothelin-1 is also released in the circulation during endotoxic shock, and antagonism of endothelin type A receptors may reduce leukocyte recruitment and gut injury [50]. Endotoxin-induced microvascular leakage occurs before leukocytes start to adhere to endothelium, and can be prevented by interventions that interfere with either Platelet Activating Factor (PAF) or nitric oxide synthase [51].


   6 Microvascular alterations in chronic diseases
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 1 Introduction
 2 Microcirculation as the...
 3 Biophysical mechanisms of...
 4 New mediators of...
 5 Microcirculation during...
 6 Microvascular alterations in...
7 Microcirculation and...
 References
 
Microvascular disorders have also been involved in the pathophysiology of chronic diseases, such as diabetes, hypertension and atherosclerosis and in aging.

Microangiopathy is a major feature of the diabetic clinical picture, as it is responsible of many long-term complications, such as retinopathy, nephropathy, and peripheral arteriopathy. The pathogenesis of microvascular alterations in diabetes has not yet been elucidated, but it is becoming evident that differences exist between type 1 and type 2 diabetes, and that endothelial dysfunction plays a major role in this phenomenon, together with pericyte alterations and hyperglycemia [52]. In addition, since insulin may affect vascular tone and smooth muscle cell proliferation, insulin resistance might also be involved in this picture. In patients with fasting hyperglycemia, that are at risk of developing non insulin-dependent diabetes, it has recently been shown that microvascular hyperemic response is impaired and it is inversely correlated with fasting insulin concentrations, suggesting that hyperinsulinemia may have detrimental effects on microvascular function in the prediabetic state [53]. Advanced glycation end-products (AGE) and their receptors (RAGE) colocalise in sites where diabetic microvascular injury is more pronounced, such as kidney, eye, nerve, arteries, suggesting that interaction of AGE and RAGE may be important in the pathogenesis of diabetic microvascular alterations [54]. In diabetic patients, there is a correlation between presence of retinopathy and reduction of coronary flow reserve, with reduction being more severe when retinopathy is present [55]. Thus, presence of diabetic retinopathy may be a marker of microvascular impairment and reduced coronary flow reserve.

As to possible mechanisms, evidence is accumulating supporting a role for pericytes in diabetic retinopathy. Diabetes leads to accelerated apoptotic death of retinal pericytes and endothelial cells [56]. This phenomenon seems specific for vascular cells and precedes histological evidence of retinopathy [56]. Interestingly, it can also be induced by isolated hyperexosemia, suggesting a role for elevated blood glucose in this phenomenon [56]. Exposure to high blood glucose induces generation of AGE, formed by non-enzymatic glycation of serum proteins, and exposure of pericytes to AGE results in selective modifications of glycoprotein sugar chains [57]. AGE also induces angiogenesis through the induction of autocrine VEGF, and thereby may play a role in development and progression of diabetic microangiopathies [58].

Hypertension is another chronic condition associated with microvascular alterations. Microvascular alterations reported in hypertension include reduced diameter and density of vessels, impaired vasodilating reserve, and increased vascular malformations [59]; all these factors have been involved in the pathogenesis of hypertension and its complications.

Dahl salt-sensitive rats develop hypertension when fed with a high salt diet. In these animals, coronary microvessels exhibit a specific pattern of endothelial impairment, since acetylcholine-induced vasodilation may still be present when response to substance P and bradykinin is blunted [60]. A similar heterogenous impairment of endothelial-dependent vasodilation has also been observed in hypertensive patients [61]. In the microvasculature of Dahl-sensitive rats, development of hypertension is accompanied by oxidant stress, and plasma hydrogen peroxide concentrations correlate with mean arterial pressure [62]. These animals also exhibit impaired renal vasodilation after high salt intake. This phenomenon seems to be related to reduced cGMP generation, and results in salt retention and development of hypertension [63].

Increased vascular resistance in hypertension occurs mostly in microvessels, and therefore many studies have investigated whether altered control of microvascular growth and function is involved in the pathogenesis of hypertension. Defective angiogenesis has been implicated in the pathogenesis of hypertension. In rats subjected to subtotal nephrectomy or to high-salt diet, reduced vessel density rapidly occurred, with a heterogeneous distribution [64]. In patients with familial essential hypertension, offspring with high blood pressure whose parents also have high blood pressure have impaired dermal vasodilation in the forearm, and fewer capillaries on the dorsum of finger [65]. Recent evidence has also suggested that chemical mediators of angiogenesis may directly influence microvascular tone. Acidic and basic fibroblast growth factors (FGFs) may also be directly involved in modulation of arterial pressure, since in rats their administration increases arterial diameter and blood flow in isolated microvessels and in arterioles of intact cremaster muscle, via nitric oxide-dependent mechanisms [66]. Complex effects on microvasculature are also exerted by angiotensin II, which has been involved in many ways in the pathogenesis of hypertension. Activation of type 1 receptors induces angiogenesis and vasoconstriction, while type 2 receptors inhibit angiogenesis and induce vasodilation [67].

Aging is also accompanied by microvascular alterations, which include reduction of elastin and smooth muscle cells, and increase in collagen content of the vessel wall; altered morphology has been described in brain microvessels [59]. A reduced ability to regulate individual organ blood flow has also been reported, although little attention has been focused on microcirculation [59]. Recently, aging has also been associated with selective impairment of endothelial function, which can be reversed by administration of L-arginine [68]. In Alzheimer patients, cerebral and meningeal microvessels display increased release of soluble amyloid protein in comparison with age-matched control [69]. Microcirculation may also be affected during atherogenesis [70]. Reduced endothelial-dependent vasodilation has been reported in isolated microvessels exposed to oxidized LDL; vasodilating response was restored by incubation with oxygen radical scavengers, suggesting a role for oxidative stress in this phenomenon [71]. Cholesterol feeding impairs microvascular function in rabbits, and these changes can be prevented by vitamin C administration. These data are compatible with previous studies showing that cholesterol induced vascular alterations could be prevented by lipid-soluble antioxidants [72].

The mechanisms by which venous hypertension induces skin ulcerations is still unclear. Data in the literature argue against an involvements of altered diffusion of oxygen and nutrients, while it has been hypothesized that leukocyte activation may be involved, with secondary endothelial injury and tissue inflammation [73]. In affected skin, microvascular changes have been reported, with endothelial activation and perivascular inflammation. Venous hypertension may induce sequestration of more activated population of neutrophils and monocytes in lower limb circulation, that would in turn result in tissue injury [74]. Increased expression of ICAM-1, which mediates adhesion of neutrophils to vascular endothelium, can be found in the skin surrounding venous ulcerations, while it is absent in the clinically unaffected skin [75]. In patients with venous ulcers, inappropriate postural vasoregulation causes relative ischemia and reperfusion, and it has thus been hypothesized that repeated episodes of ischemia–reperfusion may induce an inflammatory reaction, with leukocyte activation and recruitment, tissue injury, and formation of venous ulcers. However, postural vasoregulation does not modify release of proinflammatory mediators, suggesting that ischemia–reperfusion do not contribute to inflammatory injury in these patients [76].


   7 Microcirculation and angiogenesis
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 1 Introduction
 2 Microcirculation as the...
 3 Biophysical mechanisms of...
 4 New mediators of...
 5 Microcirculation during...
 6 Microvascular alterations in...
 7 Microcirculation and...
References
 
In the 1996 issue devoted to microcirculation there was no review on the role of microcirculation in angiogenesis. However, the mechanisms of angiogenesis and its role in a number of pathophysiological conditions have received increasing attention, documented by the number of papers (1848) that were retrieved from the Medline database for the years 1996–1998. Among these, 118 articles also involved microcirculation. Most focused on angiogenesis during tumor development, and have not been included in the present review; the role of angiogenesis in diabetes and hypertension has already been discussed.

Differences exists between micro- and macrovascular endothelium during angiogenesis. Gelatinase B is an enzyme that facilitates migration of endothelial cells during angiogenesis. The active form of gelatinase accumulates in the cytosol of microvascular endothelial cells, but not in macrovascular endothelium, where it accumulates in secretory vesicles from which it may be rapidly released [77]. In response to FGF stimulation, microvascular endothelial cells upregulate expression of urokinase-type plasminogen activator, and form capillary-like structures, while macrovascular endothelium does not [78].

Oxidative stress occurs under various conditions associated with angiogenesis, and it has been shown that it may modulate angiogenesis. Exposure to hydrogen peroxide induces angiogenesis of cultured endothelium in collagen gels [79]. This phenomenon is mediated by activation of the transcription factor NF-{kappa}B, which in turn upregulates transcription and synthesis of interleukin 8, and stimulates angiogenesis [79]. This interesting observation may account for angiogenesis induction in various pathophysiological conditions.

Taken together, studies on microcirculation have made a great contribution to our knowledge of cardiovascular physiology, and to a better understanding of a variety of cardiovascular diseases. It is conceivable that the interest will increase even further in the next years.

Time for primary review 30 days.


   References
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 1 Introduction
 2 Microcirculation as the...
 3 Biophysical mechanisms of...
 4 New mediators of...
 5 Microcirculation during...
 6 Microvascular alterations in...
 7 Microcirculation and...
 References
 

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