Parathyroid hormone-related protein was discovered in 1987 and shown to mediate humoral hypercalcemia of malignancy (HHM) a syndrome which had puzzled physicians for decades. This protein is also produced in many normal tissues where it is believed to function in an autocrine or paracrine fashion. Our studies during the last three years have established vascular smooth muscle as an important site of PTHrP production and action. We have characterized the principal mechanisms by which PTHrP is induced by vasoconstrictors and mechanical stimuli. In addition, we have demonstrated novel actions PTHrP on VSMC growth and extracellular matrix production which are mediated through PTH/PTHrP receptors. These observations have upheld our central hypothesis that locally produced PTHrP functions in vascular smooth muscle to restrict both pressor and mitogenic signals induced by vasoconstrictor and mechanical events. In essence we believe we have uncovered a novel compensatory autocrine vasoactive loop not previously appreciated. These advances, together with the discovery that PTHrP is a locally active factor who's production is vital in development, have prompted more sophisticated questions on the processing of PTHrP and the molecular mechanisms responsible for the full range of PTHrP vascular actions.
In Aim 1 of the present proposal we will structurally identify the PTHrP forms that are produced in VSMC. In a Aim 2 we will explore in vitro the mechanisms by which PTHrP inhibitors VSMC growth and modulates extracellular matrix production. We will also investigate the involvement of cell cycle related genes in PTHrP growth inhibition of VSMC. In addition, since growth inhibitory activity of PTHrP are associated with an inhibition of osteopontin expression we will determine the effect of PTHrP peptides on VSMC identified in the studies under Aim 1 will be tested for biological activity in our cell models. In the final Aim we will determine the effects of PTHrP in vascular smooth muscle in vivo in transgenic mice. Transgenic mouse models which selectively overexpress PTHrP and its receptor in smooth muscle will be used to examine two distinct functions of PTHrP. First, we will compare the development of thoracic aorta in PTHrP expressing mice, their non- expressing litter mates and int he PTHrP knock out mice using specific smooth muscle cell specific probes (DNA and protein). Secondly we will explore the possibility that overexpression of PTHrP in vascular smooth muscle alters basal and volume stressed cardiovascular hemodynamics. Collectively we believe our studies will greatly expand our understanding of the biology of PTHrP in vascular smooth muscle.
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