The Hydrogen Sulfide Donor NaHS Promotes Angiogenesis in a Rat Model of Hind Limb Ischemia

Abstract

It is not known whether H(2)S can promote angiogenesis with improvement of regional blood flow in ischemic organs. Sodium hydrosulfide (NaHS, a H(2)S donor) was administered once a day for 4 w following femoral artery ligation. Collateral vessel growth, capillary density, regional tissue blood flow, the expression of endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2) and Akt were examined during or at the end of the treatment period. NaHS treatment significantly increased collateral vessel growth, capillary density, and regional tissue blood flow in ischemic hind limb muscles compared with the controls. These effects were associated with an increase in VEGF expression in the skeletal muscles and VEGFR2 phosphorylation in the neighboring vascular endothelial cells, suggesting a role of VEGF in mediating the NaHS effects in a cell-cell interaction pattern. Moreover, NaHS treatment also resulted in an increase in Akt phosphorylation in ischemic hind limb muscles. In conclusion, our observations with NaHS strongly suggest that H(2)S is a proangiogenic factor in chronic ischemia. The proangiogenic effect of NaHS may be mediated by interaction between the upregulated VEGF in the skeletal muscle cells and the VEGFR2 as well as its downstream signaling element Akt in the vascular endothelial cells.

Hydrogen Sulfide Attenuates sFlt1-Induced Hypertension and Renal Damage by Upregulating Vascular Endothelial Growth Factor

“…32 In vivo, it was demonstrated that H 2 S is a proangiogenic factor in a model of hind limb ischemia. 33 These effects were associated with an increase in VEGF expression and activation of vascular endothelial growth factor receptor (VEGFR)2 signaling in vascular endothelial cells, suggesting that the effects of H 2 S may be mediated by VEGF and its receptor VEGFR2. 33 Bir et al recently showed that H 2 S-stimulated ischemic vascular growth is dependent on augmented expression and activity of VEGF.…”

“…33 These effects were associated with an increase in VEGF expression and activation of vascular endothelial growth factor receptor (VEGFR)2 signaling in vascular endothelial cells, suggesting that the effects of H 2 S may be mediated by VEGF and its receptor VEGFR2. 33 Bir et al recently showed that H 2 S-stimulated ischemic vascular growth is dependent on augmented expression and activity of VEGF. 34 We therefore hypothesized that by upregulating VEGF, H 2 S may directly antagonize the detrimental effects of sFlt1 on the endothelium, consequently attenuating the development of hypertension and proteinuria.…”

Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor‐Erythroid 2‐Related Factor 2 (Nrf2)‐Dependent Signaling in Chronic Heart Failure

“…Biological profiles of H 2 S and NO are similar, and both molecules are known to protect cells against various injurious states. Previous studies suggest that H 2 S augments angiogenesis under ischemic conditions both in vitro and in vivo 51, 52. Treatment with exogenous H 2 S or modulation of the endogenous production of H 2 S through the cardiac‐specific overexpression of CSE protects against acute myocardial infarction and HF by attenuating oxidative stress, inhibiting apoptosis, and reducing inflammation 34.…”

H2S in the Vasculature: Controversy of Mechanisms in Physiology, Pathology and Beyond

“…While the signaling properties under physiological conditions are being slowly uncovered, actions under pathological conditions are less defined. H 2 S has previously been described to contribute to angiogenesis [32], collateral growth [33], and vascular proliferation [34]. Under pathological conditions, these same signaling events can lead to the development of atherosclerosis, a key factor in the development of CVD.…”