Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized pathologically by pulmonary arterial and arteriolar microthrombosis, vasoconstriction, and intimal and medial hyperplasia. The mechanisms underlying PAH initiation and progression remain incompletely understood. Exploring potential novel contributors to PAH will aid in disease understanding and the development of new therapeutic targets. Evidence suggests that endothelial activation plays a crucial role in the pathogenesis of PAH. An important early consequence of endothelial activation is the release of von Willebrand Factor (VWF) from endothelial cells via exocytosis of pre-formed organelles known as Weibel-Palade bodies (WPB). VWF mediates binding between the endothelium and circulating blood components such as platelets, and promotes microvascular thrombosis and inflammation. VWF contributes to vascular dysfunction in human diseases including atherosclerosis, venous thrombosis, sepsis, and the thrombotic microangiopathies. Patients with PAH have increased levels of circulating VWF with altered multimer composition, and display increased staining for VWF within the pulmonary endothelium on autopsy. Circulating VWF levels correlate with disease severity in PAH. In studies of the systemic circulation, VWF promotes microvascular thrombosis, smooth muscle cell proliferation, and recruitment of platelets. All these processes are involved in PAH, and VWF secretion may therefore contribute to disease progression in PAH. Dr. Ying Zheng has created endothelialized bioengineered microvessels that recapitulate the architecture and flow conditions of the microvasculature and allow use of human tissues of defined origin. This research proposal focuses on applying the Zheng lab microvessel model to study VWF's behavior in the pulmonary circulation. This proposed project will characterize the expression and storage of VWF within the pulmonary endothelium, the environmental factors leading to VWF release, and the downstream effects of VWF release on the pulmonary endothelium and pulmonary vascular smooth muscle. This research proposal comprises three main aims: (1) Study VWF expression, storage, and secretion in cells of different pulmonary vascular origin (2) Evaluate how environmental conditions seen in PAH affect VWF expression, storage, and release (3) Examine the consequences of increased VWF release on vascular remodeling. This research will set the stage for future mechanistic studies on the downstream effects of VWF on the pulmonary vasculature, and may lead to the development of VWF-targeted therapeutics for the treatment of PAH. As VWF is also implicated in numerous systemic vascular diseases, this research is likely to have broad application beyond pulmonary vascular biology.
Endothelial activation with von Willebrand Factor (VWF) release contributes to many human diseases. Elevated VWF levels are observed in patients with pulmonary arterial hypertension (PAH) and correlate with mortality, but little is known about VWF's behavior within the pulmonary circulation. Understanding how the environment seen in PAH affects VWF storage and release will further understanding of the pathogenesis of PAH and may lead to new therapies for this disease.
