Parathyroid hormone-related protein (PTHrP) was discovered in 1987 and shown to mediate humoral hypercalcemia of malignancy (HHM). Subsequently, this protein was found to be produced in many normal tissues where it is believed to function in an autocrine or paracrine fashion. Recent studies in my sponsor's laboratory have established vascular smooth muscle as an important site of PTHrP production and action. PTHrP is induced by vasoconstrictors in primary vascular smooth muscle cells (VSMC) in vitro and by mechanical stimuli in vivo. Specific actions of PTHrP on VSMC have also been demonstrated including marked growth inhibitory effects which are accompanied by inhibition of extracellular matrix production. These observations have led us to hypothesize that locally produced PTHrP functions in vascular smooth muscle to restrict both pressor and mitogenic signals induced by vasoconstrictor and mechanical events. These advances, together with the discovery that PTHrP is a locally active factor who's production is literally vital in development, have prompted more refined questions on the mechanisms responsible for the global effects of PTHrP vascular actions.
In specific aim 1, the possibility that overexpression of the PTHrP gene or PTH/PTHrP receptor gene in vascular smooth muscle of transgenic mice alters basal and pressor induced cardiovascular hemodynamics will be examined by measuring baseline variables of cardiac performance and blood pressure. For these experiments we take advantage of the expertise of my co-sponsor (Dr. Richard Paul) and the newly developed cardiovascular transgenic core facility to apply novel methods for measuring blood pressures, total peripheral resistance and blood flow.
In specific aim 2, the impact of overexpression of PTHrP or PTH/PTHrP receptor gene in smooth muscle development and differentiation will be examined in vivo in these same transgenic mice using a series of smooth muscle specific markers. These studies should greatly expand our understanding of the biology of PTHrP in smooth muscle.
