|
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 C57bl/6 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 extracellular signal-regulated kinase ERK1/2 (3.15±0.14-fold of 80 mmHg, P<0.01), and activated the nuclear factor-kB (NF-kB) pathway, verified by degradation of the endogenous inhibitor I?B? (0.68±0.08-fold, P<0.05). The role of ERK1/2 and NF-kB in high pressure-induced vessel distensibility was assessed using the specific inhibitors PD98059 and pyrrolidine dithiocarbamate (PDTC), respectively. PD98059 blocked ERK1/2 activation in vessels at 150 mmHg but did not influence the pressure-diameter relationship. In contrast, PDTC prevented both the degradation of IkBa and the upward shift in the pressure-diameter curve in carotids maintained at high pressure. Fittingly, MMP induction in vessels at 150 mmHg was blocked by PDTC but not by PD98059. Furthermore, in carotid arteries from FVB mice, characterized by a lower NF-kB activity than C57bl/6 mice, high intraluminal pressure failed to enhance vessel distensibility. Hence, although both ERK1/2 and NF-kB are activated at 150 mmHg, only the latter pathway is involved in pressure-dependent induction of MMPs and the ensuing increase in vessel distensibility. Our results demonstrate that NF-kB plays a key role in regulating the early stages of hypertensive vascular remodeling.
|
J. Vasc. Biol. 42, Sup:2 (2005) p59