Pathogenic and Therapeutic Mechanisms of Pulmonary Vascular Diseases, Right Heart Failure

A Department of Medicine Research Spotlight

Professor of Medicine
Chief, Division of Translational and Regenerative Medicine
Associate Vice President for Translational Health Sciences, UA Health Sciences

The research interests of my laboratory center on pathogenic and therapeutic mechanisms of pulmonary vascular diseases and right heart failure.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that predominantly affects women. Elevated pulmonary vascular resistance (PVR) in PAH patients causes an increase in afterload in the right ventricle, leading to right ventricular hypertrophy, right heart failure, and death. Regardless of the initial genetic or pathogenic trigger, the pathogenesis of PAH can be attributed to sustained pulmonary vasoconstriction, excessive pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular stiffness resulting in elevated PVR in patients with PAH. Understanding the pathogenic mechanisms of PAH is important for developing a more effective therapeutic approach for the disease. There are three ongoing research projects in Dr. Yuan’s lab that are currently funded by the National Institutes for Health:

The thickness and tissue mass of the pulmonary artery wall are maintained at an optimal level by a fine balance between cell proliferation and apoptosis. If there is more pulmonary arterial smooth muscle cell (PASMC) proliferation, the wall thickens, narrowing the lumen and ultimately leading to vascular obliteration. The structural change leading to the pathological abnormality in the pulmonary artery is referred to as vascular remodeling. Both vasoconstriction and vascular remodeling also decrease vascular compliance which, via distention and recruitment, normally accommodates increases in CO, and increase in PVR and pulmonary arterial pressure (PAP).

Figure 2-2_Pulmonary-Vasoconstriction-and-HypertensionAn increase in cytosolic free Ca2+ ([Ca²+]cyt) in PASMC is not only a major trigger for pulmonary vasoconstriction but also an important stimulus for PASMC proliferation. Intracellular Ca²+ is a critical second messenger responsible for linking external stimuli to contraction, migration, proliferation, and gene expression. A rise in [Ca²+]cyt rapidly increases nuclear [Ca²+] ([Ca²+]n). The elevated [Ca²+]cyt and [Ca²+]n both contribute to promoting proliferation by stimulating quiescent cells to enter the cell cycle (G0→G1 phase) and by driving proliferating cells through the cell cycle (G1→S and G2→M phase) and mitosis. In addition, elevated [Ca²+]cyt, by activating kinases (e.g., CaMK, MAPK) and transcription factors (e.g., NFAT, CREB, AP-1, NF-κB), promotes transcription of genes that are necessary for cell growth (see Figure 2). A rise in [Ca²+]cyt and activated CaMK can inactivate co-repressors associated with transcription factors and potentiate gene transcription. These results indicate that an increase in [Ca²+]cyt in PASMC, due to upregulated expression and/or increased activity of Ca²+-permeable channels, can serve as a shared mechanism for sustained pulmonary vasoconstriction and severe pulmonary vascular remodeling.

Using the combined techniques of patch clamp, digital imaging fluorescence microscopy, and molecular biology, my lab is currently studying the pathogenic roles of membrane receptors, ion channels and intracellular Ca²+ signaling cascades in regulating vasomotor tone, and pulmonary vascular smooth muscle proliferation and apoptosis. Furthermore, whether and how dysfunctional voltage-gated K+ (Kv) channels and upregulated transient receptor potential (TRP) channels in PASMCs contribute to the development of pulmonary hypertension is also being investigated. The aims of the ongoing research work in the laboratory that are available for undergraduate and graduate students, medical students and residents, and pulmonary/cardiology fellows are: 1) understand the cellular and molecular mechanisms involved in acute hypoxia-induced pulmonary vasoconstriction and chronic hypoxia-mediated pulmonary hypertension, 2) investigate the genetic and epigenetic mechanisms involved in the development and progression of pulmonary arterial hypertension and right heart failure, 3) specify the cellular and molecular targets to develop therapeutic approaches for patients with pulmonary arterial hypertension or pulmonary hypertension associated with hypoxia and other lung diseases, 4) search for new therapeutic approaches for pulmonary arterial hypertension and right ventricular dysfunction, and 5) determine the genetic variances associated with the susceptibility to develop idiopathic and thromboembolic pulmonary hypertension.

*For more detailed information on the above research projects please visit our lab website at: 

Release Date: 
03/14/2016 - 5:30pm