Sixteen million Americans have type II diabetes, and vascular complications are the most common causes of morbidity and mortality in diabetic patients. Abnormalities in blood vessel constriction or dilatation (vasomotion) detected in early diabetes can result in blood flow dysregulation and increased peripheral resistance, thereby contributing to diabetic complications. We and others found that db/db and high fat diet-induced type II diabetic mice are hypertensive and vascular smooth muscle tissues isolated from these animals exhibit a significantly increased contractile response to stimuli. However, the molecular mechanisms are unknown. In preliminary studies we observed that Ca2+sensitization of contractions are significantly increased in vascular smooth muscle tissues isolated from type II diabetic mice. We found that CPI-17, PKCbetall, RhoA, and ROCK, four key players of Ca2+ sensitization signaling, are significantly up-regulated/ activated in diabetic arteries. Moreover, inhibiting PKC or ROCK diminished the enhanced Ca2+ sensitization of contractions in vascular smooth muscle tissue isolated from db/db mice. Therefore, we hypothesize that in type II diabetes, activated PKCbetall and RhoA/ROCK activate CPI-17 and thereby significantly contribute to type II diabetic vascular smooth muscle hyper-contractility and hypertension.
Specific aims are: (1) To test the hypothesis that activation of CPI-17 is responsible for enhanced Ca2+ sensitization and vascular smooth muscle hyper-contractility in db/db and diet-induced type II diabetic mice. (2) To test the hypothesis that the activation of PKCbetall and RhoA/ROCK are required for vascular smooth muscle hyper-contractility in db/db and diet-induced type II diabetic mice. (3) To test the in vivo significance of the CPI-17 in vascular smooth muscle hyper-contractility and type II diabetes-associated hypertension by using pharmacological and genetic approaches. Both in vitro and in vivo methods will be employed. Isolated small mesenteric arteries will be used to investigating isometric contractions, Ca2+ sensitization of contractions, the mRNA, protein and activities of CPI-17, RhoA/ROCK and PKC. In addition, blood pressure will be measured in mice by using radiotelemetry and carotid artery catheter. The proposed study may provide new insight into the molecular mechanisms of vascular smooth muscle dysfunction in type II diabetes and into the pathogenesis of diabetes-associated hypertension. ? ? ?
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