Copyright © 2007, European Society of Cardiology
Something is rotten in the state of angiogenesis — H2S as gaseous stimulator of angiogenesis
Experimental Cardiology, UMC Utrecht, G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
*Tel.: +31 30 250 7155; fax: +31 30 252 2693. i.hoefer{at}umcutrecht.nl
Received 4 July 2007; accepted 18 July 2007
See article by Cai et al. [7] (pages 29–40) in this issue.
The research on a new class of signaling molecules, later named gaseous transmitters or gasotransmitters, started in 1986 with the discovery that the so-called endothelium-derived relaxing factor (EDRF) is identical to nitric oxide [1]. This finding was later awarded with the Nobel Prize and NO was named "molecule of the year" in 1992. Since then, countless studies have focused on the role of NO in various processes, among which its cardiovascular effects still remain most prominent. A few years later, NO was accompanied by a second biologically active gaseous molecule, carbon monoxide (CO), recently followed by the "rotten egg gas" hydrogen sulfide (H2S), and others are likely to be discovered, expanding the family of known gasotransmitters in the future. What turns these molecules into gasotransmitters is their ability to induce either endocrine, paracrine, or autocrine effects. They are freely permeable to cell membranes and bind to receptors other than known membrane receptors, which remain to be identified. Another common feature of these 3 known gasotransmitters is their toxic effects in higher concentrations. Despite their toxicity, they are endogenously produced in significant amounts; the toxic effect level of e.g. H2S is only twice as high as the concentrations in brain tissue, demanding a delicate regulating mechanism to maintain physiological levels [2].
H2S is endogenously generated from L-cysteine by two distinct enzymes, cystathionine β-synthase (CBS) and cystathionine 
-lyase (CSE), which are responsible for the majority of H2S in mammalian tissue. The expression of CBS and CSE is partly tissue specific; some organs express both enzymes, whereas vascular H2S is mostly generated by CSE and released from vascular smooth muscle cells, apart from a minor non-enzymatic reaction [3]. In aqueous solutions, about one third of H2S remains non-dissociated at physiologic pH. The effects of H2S on the cardiovascular system are manifold. Smooth muscle relaxation and hence vasodilatation is induced by H2S through opening of KATP channels [3,4], an effect that can be antagonized by pre-incubation with KATP channel blockers. In the heart, H2S induces coronary vasodilatation at low concentrations [5]. This effect is eliminated at higher concentrations, where H2S has negative inotropic effects [5]. Furthermore, H2S and CSE have been associated with the pathogenesis of hypertension. In spontaneously hypertensive rats, CSE expression is decreased, while exogenous administration attenuated the development of hypertension [6].
In this issue of Cardiovascular Research Cai et al. describe a novel, pro-angiogenic effect of H2S [7], thereby joining the company of NO and CO as angiogenic factors [8–10]. At first sight, this seems a redundant action, but it is not. Gasotransmitters interact with each other, e.g. NO donors have previously been shown to increase the expression of CSE and the release of H2S [3]. In the current study, the authors used the H2S donor NaHS to assess its role during angiogenesis. In summary, the authors showed that H2S at physiologic concentrations induces in vitro and in vivo angiogenesis, promoting endothelial cell proliferation, adhesion, and migration, whereas higher but still non-toxic concentrations yielded no such effects. Since the effects of the gasotransmitters are so closely related, this study further tried to unravel the mechanisms involved in the observed angiogenic effects. In particular, H2S and NO are strongly interwoven. Interestingly, NO metabolite levels were not affected by the treatment, endorsing the notion that the actions of H2S and NO are not redundant. Furthermore, pro-angiogenic effects via increased growth factor expression (i.e. VEGF and angiopoietin-1) were excluded by the authors as well as effects on known angiogenic signaling molecules. cAMP or cGMP levels were not affected nor was phosphorylation of the MAP kinases ERK or p38 affected by NaHS treatment, leaving the question open via which pathway H2S exerts its pro-angiogenic actions. As Cai et al. have shown, Akt phosphorylation was significantly increased upon H2S treatment, whereas either LY 294002 or wortmannin blocked this effect [7]. Akt and its activation has previously been accredited a central role during angiogenesis, partly by inducing NO production [11–14]. Since this mechanism has been excluded by the authors, many open questions remain to be answered. What is the receptor for H2S? How is Akt activated by H2S? Does H2S bind directly to Akt or are other signaling molecules involved? What lies downstream, if neither VEGF expression nor NO synthesis are induced by H2S? Based on the study in the current issue of Cardiovascular Research the hypothesized scheme of the interaction between H2S and NO in vascular tissues [15] needs to be modified to account for the observed novel angiogenic effects of H2S. As stated by the authors, their study provides the first evidence of an angiogenic effect of exogenous H2S at physiologic concentrations, which may be used to develop novel approaches in treating ischemic diseases [7]. While this is clinically appealing, one must not forget that the safety margin of gasotransmitters and in particular of H2S is very small. It has been reasoned that the dose–response relationship is very steep at physiological concentrations before sharply transforming into a highly toxic effect [3]. Nonetheless, Cai and colleagues have found a new angiogenic effect of the yet little studied gasotransmitter role of H2S and may have identified its downstream effector Akt. Apart from NO, the other gasotransmitters CO and H2S and their signaling cascades in angiogenesis in any case merit further attention as unraveling those mechanisms not only might provide tools for stimulation or inhibition of vessel growth but might also help to better understand the way gasotransmitters modulate biological processes in general.
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