The role of Hedgehog signaling in pulmonary vascular development and remodeling ABSTRACT: 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.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a highly lethal lung disease where the pulmonary vasculature undergoes abnormal thickening to cause high blood pressure in the lung. Despite current therapies, PAH remains a progressive and debilitating condition that often leads to heart failure and death. It has been recognized that genetic programs important for embryonic development are often reactivated in adult diseases such as PAH. I have demonstrated that the Hedgehog pathway is activated in both embryonic pulmonary vascular development and adult pulmonary vascular remodeling mimicking PAH. We propose to study the effect of Hedgehog signaling in both pulmonary vascular development and remodeling mimicking PAH to determine if Hedgehog is a viable pathway for drug targeting in PAH patients.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL121146-01A1
Application #
8766755
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Colombini-Hatch, Sandra
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104