Although increased levels of
reactive oxygen species (ROS) are involved in the pathogenesis of
cardiovascular diseases, the importance of physiological ROS has also been emerging. We have previously demonstrated that endothelium-derived H2O2 is an endothelium-dependent hyperpolarization (EDH) factor and that loss of endothelial
caveolin-1 reduces EDH/H2O2 in the microcirculation.
Caveolin-1 (Cav-1) is a scaffolding/regulatory
protein that interacts with diverse signaling pathways, including angiogenesis. However, it remains unclear whether endothelial Cav-1 plays a role in ischemic angiogenesis by modulating EDH/H2O2. In the present study, we thus addressed this issue in a mouse model of hindlimb
ischemia using male endothelium-specific Cav-1 (eCav-1) knockout (KO) mice. In isometric tension experiments with femoral arteries from eCav-1-KO mice, reduced EDH-mediated relaxations to
acetylcholine and desensitization of
sodium nitroprusside-mediated endothelium-independent relaxations were noted ( n = 4~6). An ex vivo aortic ring assay also showed that the extent of microvessel sprouting was significantly reduced in eCav-1-KO mice compared with wild-type (WT) littermates ( n = 12 each). Blood flow recovery at 4 wk assessed with a
laser speckle
flowmeter after femoral artery
ligation was significantly impaired in eCav-1-KO mice compared with WT littermates ( n = 10 each) and was associated with reduced capillary density and muscle
fibrosis in the legs ( n = 6 each). Importantly, posttranslational
protein modifications by
reactive nitrogen species and ROS, as evaluated by
thiol glutathione adducts and
nitrotyrosine, respectively, were both increased in eCav-1-KO mice ( n = 6~7 each). These results indicate that endothelial Cav-1 plays an important role in EDH-mediated vasodilatation and ischemic angiogenesis through posttranslational
protein modifications by nitrooxidative stress in mice in vivo. NEW & NOTEWORTHY Although increased levels of
reactive oxygen species (ROS) are involved in the pathogenesis of
cardiovascular diseases, the importance of physiological ROS has also been emerging. The present study provides a line of novel evidence that endothelial
caveolin-1 plays important roles in endothelium-dependent hyperpolarization and ischemic angiogenesis in hindlimb
ischemia in mice through posttranslational
protein modifications by
reactive nitrogen species and ROS in mice in vivo.