Primary pulmonary hypertension (PPH) is a clinical syndrome encompassing a collection of disorders of the pulmonary vasculature in which pathologic expansion of the mesenchymal compartment obstructs pulmonary blood flow in the absence of any underlying cardiac or pulmonary parenchymal disease. While a small number of patients demonstrate clinical improvement with vasodilator therapy, the majority die within 2 to 5 years of pulmonary circulatory failure. The morphologic and physiologic vascular changes of PPH have been well described, but the specific chain of events and regulatory elements which initiate and perpetuate expansion of the vascular mesenchymal compartment are not known. In studies of ex vivo vascular specimens, animal models of PPH, atherosclerosis, and repair of vascular injury, a defined set of profibrotic growth factors are associated with expansion of the mesenchymal compartment and modulation of vascular tone. Such studies, however, have not been helpful in defining the regulatory elements involved in the genesis of the anatomic changes observed in PPH. We propose to examine one question essential to understanding the genesis of the vascular fibroproliferative response: Can increased local concentrations of a profibrotic ligand which promotes smooth muscle cell and fibroblast migration, proliferation, and matrix deposition within the vascular bed lead to pulmonary hypertension, or is concomitant vascular injury required for pulmonary hypertension to occur? To answer this question we have chosen to utilize a transgenic murine model in which endothelial cells overexpress PDGF-A. To date, a chimeric gene containing a PDGF-A construct under the direction of the von Willebrand factor (VWF) regulatory element has been inserted into the mouse genome. Founder mice incorporating the gene have been identified. Progeny of these transgenic animals will provide a model system with which to examine the role of profibrotic ligands in the genesis of the pulmonary vascular fibroproliferative response. Mice expressing the VWF/PDGF-A gene will be examined for the physiologic and morphologic changes which occur in the pulmonary vascular bed over time and in response to established models of pulmonary vascular injury. Potential therapeutic strategies for patients with PPH hinge on determining whether interdiction of profibrotic ligands can prevent maladaptive vascular fibroproliferation, or whether preventing injury to the vascular bed must be the primary clinical goal. Our objective is to provide experimental evidence to guide in developing therapies for a group of diseases that remains largely refractory to current medical treatment. Working as the primary investigator on this project and the interacting with my co-sponsors will increase my knowledge of vascular biology as it relates to the spectrum of pulmonary vascular disease. My goal with this project is to acquire the skills and knowledge required to become and independent investigator and advance my career as an academic physician.
