Mechanisms for enhanced endothelium-derived hyperpolarizing factor-mediated responses in microvessels in mice

Endothelium-derived relaxing factors play an important role in cardiovascular homeostasis. Among them, endothelium-derived hyperpolarizing factor (EDHF) is important especially in microcirculation. It has previously been demonstrated that endothelium-derived hydrogen peroxide (H(2)O(2)) is an EDHF in animals and humans and that endothelial nitric oxide synthase (eNOS) plays diverse roles as a nitric oxide (NO) generating system in conduit arteries and as an EDHF/H(2)O(2) generating system in microvessels. As compared with NO-mediated responses, those by EDHF are resistant to atherosclerosis, contributing to the maintenance of cardiovascular homeostasis. The aim of this study is to elucidate the molecular mechanisms for enhanced EDHF-mediated responses in microvessels.

This study used male wild-type mice and caveolin-1-deficient mice (caveolin-1(-/-) mice). In the endothelium, eNOS was functionally suppressed in mesenteric arteries (microvessels) compared with the aorta (conduit arteries), for which Ca(2+)/calmodulin-dependent protein kinase kinase β (CaMKKβ) and caveolin-1 are involved, as EDHF-mediated responses were inhibited by STO-609 (an inhibitor of CaMKKβ) and in caveolin-1(-/-) mice, respectively. In vascular smooth muscle, relaxation responses to H(2)O(2) were enhanced through a protein kinase G1α (PKG1α)-mediated mechanism in mesenteric arteries compared with the aorta, as they were inhibited by Rp-8-Br-cGMPS (an inhibitor of PKG1α).

These results indicate that CaMKKβ, caveolin-1, and PKG1α are substantially involved in the mechanisms for the enhanced EDHF-mediated responses in microvessels in mice.