Targeting Cellular and Molecular Mediators of Pathologic Biomechanical Remodeling in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a deadly, insidious illness of the pulmonary vasculature with no effective treatment. Until the mechanisms that drive disease progression and small vessel remodeling are better understood, the rational selection of targets for disease-modifying medications will remain an elusive goal. This Doctoral Thesis aims to present novel findings on both the molecular and cellular mechanisms that drive proliferative vascular remodeling during PAH pathogenesis, with an emphasis on mediators of biomechanical changes in the vessel wall. The project is subdivided into two specific aims: (1) Test the hypothesis that antagonism of the serotonin 2B receptor inhibits small vessel remodeling and the development of familial PAH through a Src-kinase dependent mechanism; and (2) Test the hypothesis that proangiogenic hematopoietic cells mediate pathologic biomechanical remodeling in a manner dependent on serotonin 2B receptor signaling. To begin, a concise background on vessel biomechanics in pulmonary hypertension, molecular mediators of vessel stiffening in PAH, and hematopoietic cell contributions to vessel remodeling is provided. The findings for each aim are then considered separately along with a focused introduction and set of materials and experimental methods used to interrogate the hypothesis at hand. The dissertation concludes with a discussion on the impact and limitations of the work as well as a far-reaching consideration of potential future directions made possible by these findings. It is the author’s sincere hope that this body of work contributes in some small but meaningful way to the advancement towards an effective therapy for PAH that is so desperately needed by the patients and families afflicted.