Abstract 976: Early Hypertensive Vascular Remodeling is Mediated by NF-kappaB but not ERK1/2
Arterial hypertension leads to vessel wall remodeling, including altered extracellular matrix composition. We have recently shown that matrix metalloproteinases (MMPs) are implicated in this process, but the pathways leading to pressure-dependent MMP upregulation remain unknown. In mouse carotid arteries maintained in organ culture for 3 days, we found that high intraluminal pressure (150 mmHg) induced both MMP-2 and MMP-9 activity, associated with a shift in the pressure-diameter curve toward greater distensibility (p<0.01), compared with vessels maintained at 80 mmHg. High pressure also stimulated ERK1/2 (3.15+0.14-fold, p<0.01), and activated the NF-kappaB pathway, verified by degradation of IkappaBalpha (0.68+0.08-fold, p<0.05) and by increased NF-kappaB phosphorylation (p<0.0001). The specific ERK inhibitor PD98059 blocked ERK1/2 activation in vessels at 150 mmHg but did not influence the pressure-diameter relationship. In contrast, the NF-kappaB inhibitor PDTC prevented both the degradation of IkappaBalpha and the upward shift in the pressure-diameter curve in carotids maintained at high pressure. Fittingly, MMP-2 and MMP-9 activation in vessels at 150 mmHg was blocked by PDTC but not by PD98059. Furthermore, mechanosen-sitive MMP-9 expression was also inhibited by PDTC (p<0.05). Hypertensive remodeling was verified in mice treated during 1 week with of 1 microg/kg/min angiotensin II (AngII). In wild-type mice, AngII treatment induced vascular MMP activity, cell proliferation and wall thickening, and enhanced vessel distensibility. However, these responses were abolished in TGF-alpha mutant mice, that we found to have low vascular NF-kappaB activity in response to pressure, and in MMP-9−/− mice. Hence, although both ERK1/2 and NF-kappaB are activated in hypertensive conditions, only the latter pathway is involved in pressure-dependent induction of MMPs and the ensuing increase in vessel distensibility and thickening. Our results demonstrate that NF-kappaB plays a key role in regulating the early stages of hypertensive vascular remodeling.