Editors' ChoicePhysiology

Two Gases Required for Vasodilation and Angiogenesis

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Science Signaling  12 Jun 2012:
Vol. 5, Issue 228, pp. ec163
DOI: 10.1126/scisignal.2003302

The gasotransmitters hydrogen sulfide (H2S) and nitric oxide (NO) trigger dilation of blood vessels (called vasodilation) and angiogenesis, which requires proliferation and migration of endothelial cells. Cystathionine-γ-lyase (CSE) is one of the enzymes required for synthesis of H2S, and an endothelial cell–specific isoform of NO synthase (eNOS) generates NO. NO binds to soluble guanylyl cyclase (sGC), thereby generating the second messenger cyclic guanosine monophosphate (cGMP), which activates protein kinase G (PKG). The phosphodiesterase PDE5A degrades cGMP. Coletta et al. (also see Wang) describe an interdependence between NO- and H2S-mediated signaling in endothelial cells. In response to sodium hydrosulfide (NaHS), which produces H2S, microvascular endothelial bEnd3 cells treated with the NOS inhibitor L-NAME did not proliferate and aortic rings from eNOS–/– mice did not show microvessel outgrowth. Conversely, transfection of shRNAs directed against CSE attenuated proliferation and migration (as assessed by a wound scratch assay) in bEnd3 cells in response to the NO donor DEA/NO and reduced vessel outgrowth in rat aortic ring explants in response to DEA/NO and vascular endothelial growth factor (VEGF). Transfection of CSE shRNA in aortic ring explants reduced vasodilation (an effect that was rescued by exogenous application of cGMP) and attenuated increases in cGMP concentrations or phosphorylation of the PKG substrate VASP in response to acetylcholine, DEA/NO, or VEGF. In addition, vasodilation in response to NaHS treatment was decreased in aortic rings from eNOS–/– mice and in those from wild-type mice by inhibiting eNOS (with L-NAME) or PKG (with DT-2). In vitro assays indicated that NaHS inhibited the activity of the phosphodiesterase PDE5A. Both NaHS and DEA/NO treatment of bEnd3 cells increased the phosphorylation of VASP, and the PKG inhibitor DT-2 decreased proliferation and migration of bEnd3 cells and microvessel outgrowth from aortic ring explants. Furthermore, NaHS treatment of bEnd3 cells increased the phosphorylation of eNOS at Ser1177 (an activating event) and reduced phosphorylation at Thr495 (an inhibitory event). Intraperitoneal injection of NaHS increased the vascularization of matrigel plugs implanted in wild-type mice but not in eNOS–/– mice. Angiogenesis occurs during wound closure, and healing of burn wounds in rats (as indicated by smaller wound areas) was improved by topical application of NaHS, an effect that was attenuated by inhibiting eNOS with L-NAME. Thus, NO and H2S signaling synergize to promote vasodilation and angiogenesis in endothelial cells by increasing cGMP-dependent signaling.

C. Coletta, A. Papapetropoulos, K. Erdelyi, G. Olah, K. Módis, P. Panopoulos, A. Asimakopoulou, D. Gerö, I. Sharina, E. Martin, C. Szabo, Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc. Natl. Acad. Sci. U.S.A. 109, 9161–9166 (2012). [PubMed]

R. Wang, Shared signaling pathways among gasotransmitters. Proc. Natl. Acad. Sci. U.S.A. 109, 8801–8802 (2012). [PubMed]

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