Abstract MP09: Vascular Rho-kinase Activation by Inflammatory Signaling Mediates Blood Pressure Increase in Overweight

Abstract

Background: Overweight is associated with a high prevalence of hypertension. The mechanisms linking overweight to blood pressure increase remain unclear. We hypothesized that vascular Rho-kinase activation contributes to blood pressure increase in overweight by involving TNF-α and TLR4. Methods: C57/BL6 mice fed a high-fat diet for 2 weeks were used to induce overweight associated blood pressure increase. Additional treatment in overweight and normal weight mice contained Rho-kinase inhibitors (fasudil and pravastatin; n=7/all groups), etanercept and TNFR1 and TLR4 null-mice. Microvascular studies were performed in a wire myograph and arterial blood pressure measured with a carotid catheter. Rho-kinase activity was determined in small mesenteric arteries of all groups. Inflammatory ligands such as TNF-alpha and free fatty acids were determined. Effects of TNF-alpha and TLR4 ligand LPS and palmitic acid on Rho-kinase activity and were determined ex vivo in mesenteric arteries and in in vivo. Results: Overweight mice had higher blood pressure (Delta: 9±2 mmHg) and vasoconstriction as normal weight mice. Small mesenteric arteries of overweight mice had a 50% higher Rho-kinase activity as normal weight mice. Ex vivo treatment with the Rho-kinase inhibitor Y-27632 reversed vasoconstriction of mesenteric arteries of overweight mice to constriction level in normal weight mice. In vivo treatment with the Rho-kinase inhibitor fasudil or pravastatin along with high-fat diet abolished the overweight associated blood pressure increase and enhanced vasoconstriction. TNF-alpha and TLR4 ligand free fatty acid were enhanced in overweight mice. TNF-alpha and TLR4 ligand LPS and palmitic acid increased Rho-kinase activity in mesenteric arteries. Use of etenercept, TNFR1 and TLR4 null-mice in the overweight model prevented blood pressure increase, vasoconstriction and Rho-kinase activation. All described effects were independent of adiposity. Conclusion: These results indicated that in diet-induced overweight vascular Rho-kinase activation is a key element of increased blood pressure and vasoconstriction. Potential activator of Rho-kinase are mediated by inflammatory factors including TLR4 ligands and TNF-alpha.