Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Remodeling

Abstract

Blockage or restriction of blood flow through conduit arteries results in tissue ischemia downstream of the disturbed area. Local tissues can adapt to this challenge by stimulating vascular remodeling through angiogenesis and arteriogenesis thereby restoring blood perfusion and removal of wastes. Multiple molecular mechanisms of vascular remodeling during ischemia have been identified and extensively studied. However, therapeutic benefits from these findings and insights are limited due to the complexity of various signaling networks and a lack of understanding central metabolic regulators governing these responses. The gasotransmitters NO and H2 S have emerged as master regulators that influence multiple molecular targets necessary for ischemic vascular remodeling. In this review, we discuss how NO and H2 S are individually regulated under ischemia, what their roles are in angiogenesis and arteriogenesis, and how their interaction controls ischemic vascular remodeling.

The role of endoglin in post-ischemic revascularization

“…ECs exposed to prolonged laminar shear stress undergo configurational changes in surface adhesion receptors (including selectins and integrins). These changes result in cytoskeletal remodeling and subsequent activation of signal transduction pathways, ultimately leading to an anti-apoptotic state and increased release of the vasodilator NO by activation and expression of all NOS isoforms (eNOS, iNOS and nNOS) [72,73]. NO plays a major role in stimulating arteriogenesis, as its inhibition markedly reduces the effects of increased FSS, whereas all NOS isoforms are significantly upregulated both at the transcriptional and at the translational level [73].…”

“…These changes result in cytoskeletal remodeling and subsequent activation of signal transduction pathways, ultimately leading to an anti-apoptotic state and increased release of the vasodilator NO by activation and expression of all NOS isoforms (eNOS, iNOS and nNOS) [72,73]. NO plays a major role in stimulating arteriogenesis, as its inhibition markedly reduces the effects of increased FSS, whereas all NOS isoforms are significantly upregulated both at the transcriptional and at the translational level [73]. Deletion of both eNOS and iNOS leads to complete loss of collateral vessel remodeling upon femoral arterial occlusion [74,75].…”

Hydrogen Sulfide-Preconditioning of Human Endothelial Progenitor Cells Transplantation Improves Re-Endothelialization in Nude Mice with Carotid Artery Injury

“…It was speculated that NO was imperative for H 2 S to exert protective effects [29, 30] , therefore, we evaluated NO level in the conditioned media at 48h of NaHS stimulation. As shown in the Figure 2B, NaHS promoted NO production in a dose-dependent manner.…”

Diabetic keto acidosis as a deceiving presentation to simultaneous aortic and tricuspid infective endocarditis

“…In this study, removal of the endothelium with saponin did not affect maximum H 2 S-induced relaxation of rat aortic rings but require higher concentrations of H 2 S to elicit a response suggesting the endothelium is a potential target of H 2 S. Other studies, however, have observed a significant role of the endothelium in H 2 Sinduced vasodilation. Our group reported a dramatic loss of sodium hydrogen sulfide (NaHS)-induced dilation in endothelium-denuded mesenteric arteries [21]. NaHS-induced dilation is also abrogated in arteries after luminal application of the BK Ca inhibitor, iberiotoxin (IbTX).…”

“…Thus, the synthesis of this gasotransmitter is not completely defined and remains an area of active investigation as discussed below. After synthesis and release, H 2 S has effects in the vascular wall that include inhibition of inflammation [13][14][15][16][17], stimulation of angiogenesis [18][19][20][21][22], increased production of endothelium-derived relaxing factors [23][24][25], activation of antioxidant pathways [26], and direct stimulation of vascular smooth muscle cell vasodilation [8,27,28]. These pathways will be discussed below along with a discussion of H 2 S production and activity in several cardiovascular diseases.…”