The long-term objective is to better characterize the mechanisms underlying the vascular remodeling seen in hypertension. The current focus is to identify the pressure-induced intracellular signal transduction pathways and ultimate upregulation of various growth factors leading to vascular smooth muscle cell (VSMC) hypertrophy. In order to study signal transduction, pairs of rat mesenteric and human arteries (from surgical discard) will be isolated, mounted, and pressurized to hypertensive levels in a dual-vessel chamber. At various time intervals, these vessels will be examined for phosphorylated (i.e. activated) signal-dependent kinases. By western blotting with phosphorylation-specific antibodies to various kinases (Erk1/2, JNK, p38) in a temporal manner, the investigators hope to establish the pressure-induced signaling pathway. Preliminary data from their lab suggests that Platelet Derived Growth Factor (specifically PDGF-AA) is upregulated in response to hypertension and may play a role in the hypertrophy of VSMCs. To examine this further, the investigators have designed a specialized catheter to deliver PDGF-AA directly onto the carotid media of normotensive rats. Next, hypertensive rats treated with either a PDGF-AA receptor blocker or the antisense mRNA to PDGF-AA will be used to identify vascular hypertrophy that may occur in the absence of PDGF-AA. The investigators believe that the knowledge gained from these experiments may be used for the development of novel therapeutics for the treatment of hypertension and prevention of long term complications.
