Important Role of Endothelial Caveolin-1 in the Protective Role of Endothelium-dependent Hyperpolarization Against Nitric Oxide-Mediated Nitrative Stress in Microcirculation in Mice.

AIMS: Nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) play important roles in maintaining cardiovascular homeostasis. We have previously demonstrated that endothelial NO synthase (eNOS) plays diverse roles depending on vessel size, as a NO generating system in conduit arteries and an EDH-mediated system in resistance arteries, for which caveolin-1 (Cav-1) is involved. However, the physiological role of endothelial Cav-1 in microvessels remains to be elucidated.

METHODS AND RESULTS: We newly generated endothelium-specific Cav-1-knockout (eCav-1-KO) mice. eCav-1-KO mice showed loss of endothelial Cav-1/eNOS complex and had cardiac hypertrophy despite normal blood pressure. In eCav-1-KO mice, as compared to wild-type controls, the extent of eNOS phosphorylation at inhibitory Thr495 was significantly reduced in mesenteric arteries and the heart. Isometric tension and Langendorff-perfused heart experiments showed that NO-mediated responses were enhanced, whereas EDH-mediated responses were reduced in coronary microcirculation in eCav-1-KO mice. Immunohistochemistry showed increased level of 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), a marker of nitrative stress, in the heart from eCav-1-KO mice. S-guanylation of cardiac H-Ras in eCav-1-KO mice was also significantly increased compared with wild-type controls.

CONCLUSIONS: These results suggest that eCav-1 is involved in the protective role of EDH against nitrative stress caused by excessive NO to maintain cardiac microvascular homeostasis.