Changes in the Regulation of Cerebral Vasoactive Reactions in Aging: The Contribution of H2S to cGMP-Induced Dilation

The signaling cascade “NO → soluble guanylate cyclase (sGC) → cyclic guanosine monophosphate (cGMP) → protein kinase G (PKG)” plays a significant role in vascular dilation, and its dysfunction can cause the development of cerebrovascular diseases. The key element in the NO → PKG signaling system is cGMP. Intracellular cGMP levels are largely regulated by cGMP-hydrolyzing phosphodiesterase (PDE) enzymes that break down cGMP. Aging is accompanied by a decrease in NO synthesis and cGMP levels and an increase in PDE activity. Under these conditions, it is possible to increase the contribution of compensatory mechanisms of the activation of individual sections of the NO → PKG signaling pathway, in particular with the participation of intermediaries that change the cGMP level. Hydrogen sulfide (H₂S) is currently considered one of the activators of the NO → PKG pathway, which can increase cGMP levels in cells by inhibiting PDE or its direct interaction with cGMP to form biologically active compounds that are less susceptible to enzymatic breakdown. H₂S-mediated cGMP activation has been shown in cardiomyocytes and smooth muscle cells of the mesenteric and aortic vessels, but this mechanism has not been studied in cerebral vessels. The aim of the work is to study the contribution of H₂S to the regulation of cGMP-induced vasodilation in cerebral vessels and how this mechanism of regulation changes with aging. In Sprague-Dawley 4 (young) and 18-month-old (aging) rats, a comparative study of the dilatation of pial arteries to the effect of 8-Br-cGMP (8-bromine-cyclic guanosine monophosphate), which is a cell-permeable analog of cGMP, is performed using intravital microphotography, and an assessment of the effect of exogenous (donor is NaHS) and endogenous H₂S on the cGMP-induced vasodilation is carried out. Propargylglycine is used as a blocker of endogenous H₂S. It is shown that in 4-month-old rats, the H₂S-mediated regulation of cGMP-induced dilation of pial arteries is expressed only at the level of large arteries with a diameter of more than 40 μm. Aging leads to an increased contribution of endogenous H₂S to the cGMP-induced dilation of pial arteries of all calibers and an increased sensitivity of cGMP-mediated reactions of small pial arteries to exogenous H₂S.