The roles of Hedgehog signaling in pulmonary vascular development and remodeling

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The recapitulation of embryonic programs characterizes a variety of diseases that manifest abnormal cellular proliferation. Unraveling the biological complexity of embryonic vascular development has the potential to provide better understanding of the pathogenesis of adult vascular diseases such as pulmonary arterial hypertension (PAH). Vascular compartments in patients with PAH exhibit abnormal proliferative capacity that causes maladaptive remodeling of the pulmonary vasculature and obliteration of the vascular lumen. Aberrant proliferation in normally quiescent tissue compartments such as the pulmonary vasculature often reactivates embryonic programs that drive proliferation and differentiation during normal development. Sonic Hedgehog (Shh) is a master regulator of tissue-tissue interaction and cell fate during embryonic development. Interestingly, Hedgehog signaling has also been studied in a wide range of adult diseases ranging from fibrosis to cancer, culminating in the recent approval of a Hedgehog inhibitor to treat patients with basal cell carcinoma. However, the role of Shh in driving the proliferation and differentiation of pulmonary vascular compartments during embryonic development, and how this might relate to adult pulmonary vascular disease is less clear. In my preliminary studies, I demonstrated that Shh activates a novel population of multipotent cardiopulmonary progenitors (CPPs) within the cardiogenic mesoderm during development. These CPPs clonally generate multiple compartments of the pulmonary vasculature and the heart. Deletion of Hedgehog signaling within CPPs causes pulmonary vascular hypoplasia with loss of vascular smooth muscle cell (VSMC) differentiation. I also showed that Hedgehog signaling continues to activate adventitial progenitors in the adult pulmonary vasculature that are capable of proliferating and differentiating into VSMCs in an animal model of PAH. These data suggest that CPPs and adventitial cells are VSMC progenitors in normal development and abnormal vascular remodeling respectively, with both activated by Hedgehog signaling. Therefore, I hypothesize that Shh plays potentially parallel roles in normal pulmonary vascular development and abnormal vascular remodeling by promoting VSMC progenitor proliferation and differentiation in both clinical contexts. I will address this hypothesis by examining the effect of Hedgehog deletion in VSMC progenitors in both embryonic pulmonary vascular development and in an animal model of PAH. Mechanistic understanding generated from this proposal could provide a strong rationale for therapeutic targeting of the Hedgehog pathway in patients with PAH. Furthermore, successful completion of this proposal would provide me with the crucial training to become an independent investigator in pulmonary vascular biology and disease.