Work

Vascular diameter determines sensitivity to soluble guanylate cyclase activation in human mesenteric and renal arteries

Year: 2025

Type: article

Abstract: Objective This study tested if arterial reactivity to soluble guanylate cyclase (sGC)/protein kinase G (PKG) pathway activation depends on age, vessel localization as well as diameter and investigated the molecular mechanisms involved in sGC activator-induced vasodilation in human arteries. Methods sGC/PKG were stimulated by sodium nitroprusside (SNP) or the sGC activator cinaciguat. Mesenteric and intrarenal arteries from young and aged mice as well as from patients who underwent elective colon resection or nephrectomy were investigated by wire myography. Phosphorylation of the regulatory 20-kDa light-chain of myosin at serine 19 (MLC 20 -S19) and targeting-subunit-of-myosin-phosphatase at threonine 853 and serine 668 (MYPT1-T853 and MYPT1-S668) were determined by Western blot. Results In murine vessels, SNP- and cinaciguat-induced vasodilation was significantly less in intrarenal than in mesenteric arteries and not age-dependent. Human intrarenal and mesenteric arteries showed a similar vasodilation in response to SNP and cinaciguat. In both vascular beds arteries with a lumen diameter < 700 μm showed a stronger cinaciguat-induced vasodilation than arteries with a lumen diameter > 700 μm. Cinaciguat (0.1 μmol/l) increased PKG-dependent MYPT1-S668 phosphorylation in <700 μm vessels but not in >700 μm vessels. Cinaciguat significantly reduced MLC 20 -S19 phosphorylation only in <700 μm mesenteric arteries. Conclusions In contrast to murine arteries, SNP- and cinaciguat-induced vasodilation is similar in human intrarenal and mesenteric arteries. In the human vasculature, small diameter arteries are more responsive to sGC activation than large diameter vessels irrespective of the degree of MLC 20 -S19 phosphorylation.

Source: Vascular Pharmacology

DOI: 10.1016/j.vph.2025.107515