Abstract 232: Vascular Dysfunction Induced By High Pressure Levels Is Mediated By Rac-1
Oxidative stress plays a crucial role in the vascular dysfunction present in hypertension. The molecular mechanism involved are not completely elucidated. One of the principal source of oxidative stress at vascular level is the NADPH oxidase enzyme which needs Rac-1 to be activated. Aim of our study was to evaluate the role of Rac-1 in vascular dysfunction induced by high pressure levels. To test this hypothesis, carotid of mice were placed on pressure system and subjected to increasing levels of pressure (100 and 180 mmHg). In particular, after a period of perfusion (1h) with 100 mmHg vessels were subjected to 180 mmHg for three hours. At the end of perfusion period the vascular reactivity was tested. Our results demonstrate that vessels perfused with 180mmHg (n=8) showed an impaired vasorelaxation to acetylcholine as compared to vessels perfused with 100 mmHg (n=7) (% max vasorelaxation: 47±3 vs 88±7, p<0.01). Vasorelaxation to nitroglycerin was comparable between vessels perfused respectively at 100 and 180 mmHg. Some vessels were used to evaluate oxidative stress (n=5) by dihydroethidium and Rac-1 activity (n=8) by Rac-1/PAK complex. Our results demonstrate that high pressure levels induced an increased oxidative stress and more interesting an increased Rac-1 activity as compared to vessels perfused with 100 mmHg. Thus, to clarify the role of Rac-1 in high pressure evoked oxidative stress and vascular dysfunction, some vessels (n=6) were infected with adenoviral vector containing Rac-1 dominant negative. In this experimental setting vessels perfused at 180 mmHg showed an oxidative stress and endothelial vasorelaxation comparable to that observed at 100 mmHg (% max vasorelaxation: 79±6 vs 85±7, n.s.), thus demonstrating a key role of Rac-1 in oxidative stress and endothelial dysfunction evoked by high pressure levels. Thus, Rac-1 could represent the target of novel therapeutic strategies for reducing vascular damage in hypertension.