Lung Vascular Pathobiology and Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that predominantly affects women.

Pulmonary arterial hypertension constitutes a heterogeneous group of clinical entities sharing similar pathogenic mechanisms that are categorized as idiopathic PAH, heritable PAH, associated PAH, persistent pulmonary hypertension of the newborn (PPHN), and pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH). Other types of pulmonary hypertension (PH) include PH due to left heart diseases, PH due to lung diseases and/or hypoxemia, chronic thromboembolic pulmonary hypertension (CTEPH) and PH with unclear multifactorial mechanisms (e.g., PH associated with sarcoidosis, vasculitis, or tumoral obstruction).

Figure from "Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling."The elevated pulmonary arterial pressure (PA pressure) in patients with PAH is mainly due to an increase in pulmonary vascular resistance (PVR). The increased PVR in patients with PAH is caused by i) sustained pulmonary vasoconstriction, ii) pulmonary vascular remodeling characterized by concentric pulmonary vascular wall thickening due primarily to muscularization of peripheral arteries and pre-capillary arterioles, medial hypertrophy of small arteries and arterioles, neointima formation, iii) in situ thrombosis and iv) increased pulmonary vascular wall stiffness. In the later stages of the disease, endothelial cell proliferation and endothelial-to-mesenchymal transition (EndMT) lead to the development of plexiform lesions, an important feature in some patients with idiopathic and heritable PAH. The pulmonary vascular structural changes in pulmonary hypertension are collectively referred to as pulmonary vascular remodeling.

One of the research emphases in the Division of Translational and Regenerative Medicine is focused on elucidating the genetic and pathogenic mechanisms underlying the development and progression of pulmonary hypertension and on developing new therapies for this devastating disease. Work is focused on understanding the mechanisms underlying the development of the endothelial dysfunction that precedes the development of pulmonary hypertension, the role of reactive oxygen species (ROS) in this process, and understanding how decreased NO signaling leads to the pulmonary vascular remodeling that is associated with more advanced disease. In addition, work has been done on the pathogenic role of membrane receptors, ion channels and Ca2+ signaling in the development of pulmonary hypertension and genetic variations associated with idiopathic pulmonary arterial hypertension.

Related lines of research in our division currently include:

Investigators: Stephen M. Black, PhD; Ankit Desai, MD; Joe G. N. “Skip” Garcia, MD; Jason Yuan, MD, PhD; Ruslan Ravikov, PhD; Olga Ravikova, MD, PhD; Xutong Sun, PhD; Haiyang Tang, PhD; and Jian Wang, MD