Hypertension and associated cardiovascular diseases will cause more deaths in the United States than all other causes combined, with hypertension affecting more people than any other chronic disease. Patients suffering from hypertension may exhibit changes in vascular reactivity, altered compliance of heart and blood vessels and hyperplasia of smooth muscle in the walls of heart and blood vessels. Although many factors affecting the development of hypertension have been identified, the mechanisms by which these factors alter blood pressure are not well understood. The diverse nature of the factors affecting hypertension argue against the involvement of a common mechanism, however, one feature that all forms of hypertension share by definition is elevation of blood pressure. Hypothesis: This proposal submits that the increase in force exerted on vascular smooth muscle during elevation of blood pressure, will lead to changes in stretch of smooth muscle, changes in contractility of smooth muscle and hypertrophic and hyperplastic growth of smooth muscle within the vasculature. Changes in intracellular signaling associated with these events will lead to elevated secretion of neurotrophic factors like NGF. Changes in neurotrophic factor supply will lead to alterations in form and function of neurons innervating the vasculature and may cause changes in neuronal circuits extending into the spinal cord and brain. A critical component of this hypothesis is that once formed, these new synapses will be difficult to break and may thus represent a point of no return in the development of hypertension.
The proposed experiments will examine trophic interactions between vascular smooth muscle and neurons innervating blood vessels during development of hypertension in Dahl salt-sensitive (SS/Jr) rats, a model of hypertension that has both genetic and environmental components and in rats made hypertensive by treatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), a model of hypertension which has no genetic component. Changes in neurotrophic factor expression will be correlated with changes in sympathetic and sensory innervation of vasculature. The ability of pharmacological manipulations to modify or prevent the changes observed will be investigated. Studies will be performed in vivo and in vitro in cultured smooth muscle. Neurotrophic factor mRNA and protein will be measured using reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immuno assays (ELISA), respectively. Sympathetic and sensory innervation will be examined using histochemical and immunohistochemical techniques.
The results will provide information describing trophic interactions between neurons and vascular smooth muscle in hypertensive disease states. If the development of high blood pressure in these different models is associated with increased NGF expression by vascular smooth muscle and rearrangement of neuronal circuits innervating blood vessels, then this will provide strong support that the proposed mechanism may be a common component of hypertension in general. Results of these studies could provide insight into potential therapies or sites for pharmacological manipulation.