Misguided angiogenesis, plexiform pulmonary hypertension

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Primary pulmonary hypertension (PPH) is a devastating disease that occurs in a familial and a sporadic form, sometimes associated with AIDS, anorexigen drug intake and with chronic liver disease. We have found that PPH is categorically different from plexogenic secondary pulmonary hypertension (2nd PH) in that the proliferative endothelial cells in PPH are monoclonal, whereas they are strictly polyclonal in secondary PH. We postulate that the exuberant endothelial cell proliferation in severe pulmonary hypertension occurs - at least in part -because of mutations of endothelial cell genes involved in apoptosis and growth control. We further postulate that the pathogenesis of PPH can be understood by investigating the concept of misguided vasculogenesis/angiogenesis. Our approach will be to compare pulmonary vascular lesions from patients with PPH that are monoclonal with those from patients that are polyclonal and analyze (using the microarray gene chip technology), the expression pattern in these and in normal lung tissue. The DNA obtained from pulmonary hypertensive vascular lesions will be extracted and subjected to mutational analysis. The focus of the mutational analysis will be on genes associated with endothelial cell growth and apoptosis control. In order to assess the functional importance of VEGF in the development of endothelial cell proliferation and formation of obliterative lesions in PPH lungs we plan to examine to what degree ECV cells that proliferate under high shear stress conditions express an angiogenesis gene pattern. We postulate that endothelial cells which carry a mutation of the TGF-B II gene have a growth advantage and that they will seed at sites of pulmonary arterial bifurcations after they have been injected into the tail vein of nude mice. We will grow circulating endothelial cells from patients with PPH and 2nd PH in culture and examine whether they seed the lung circulation of nude mice and form obliterating lesions.