From the pulmonary arteries to the right heart: a multi-scale approach to understanding
pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is caused by adverse idiopathic remodeling of the pulmonary arteries, is ~3X more prevalent in women, and results in 5-year survival <50% due to right-ventricular (RV) failure. There are no therapies to prevent RV failure or reverse vascular remodeling in PAH. We use multi-scale experimental and computational modeling that spans from organ-scale in-vivo physiology and hemodynamics to tissue-scale structural and mechanical analysis and molecular studies of cell mechanosignaling. Using sugen-hypoxia rats, we showed for the first time that the progression of arterial and ventricular tissue remodeling differ significantly between in males and females. While many studies focus on smooth muscle cells in small pulmonary arteries, our new experiments and models showed that extracellular matrix (ECM) remodeling in the adventitia of large pulmonary arteries is a major contributor to decreased compliance and hypertension. In-vitro studies and computational models of mechanosignaling in pulmonary arterial adventitial fibroblasts showed that profibrotic signaling and gene expression in these cells are regulated by stretch and substrate stiffness. However, the threshold for theseresponses is significantly greater in female than male cells, consistent with the less severe pulmonary hypertension measured in female animals and patients. In the heart, in-vivo measurements, and computational modeling show that while the male RV relies on hypertrophy to maintain compensated systolic function, female rats recruit increased myocyte contractility and hypertrophy less. While male rats developed increased filling pressures and profound myocardial matrix stiffening, female rats were protected from this fibrotic remodeling. In isolated cardiac myocytes, calcium handling had a higher functional reserve in females compared with males, and RV fibroblasts show distinct mechanosignaling responses from left-ventricular cells. These experimental and computational results suggest a new paradigm in the pathophysiology of PAH and key differences in mechanisms and outcomes between males and females.
Dr. Daniela Valdez-Jasso is Assistant Professor of Bioengineering at the University of California San Diego. She received her Bachelor’s degree in Applied Mathematics in 2005, her Master’s degree in Applied Mathematicsin 2008, and her doctorate in Biomathematicsin 2010 all at North Carolina State University. Her graduate thesis was recognized for its excellence with a Lucas Research Award. During her postdoctoral training at the University of Pittsburgh School of Medicine, she was an American Heart Association postdoctoral fellow, and a member of the Vascular Medicine Institute and the McGowan Institute for Regenerative Medicine.
In 2013, she was appointed as an Assistant Professor of Bioengineering at the University of Illinois at Chicago, where she established her research laboratory in biomechanics, mechanobiology and multi-scale mathematical modeling of the heart and lung in a serious disease known as pulmonary arterial hypertension. In 2017, she was recruited to the Bioengineering Department at the University of California San Diego. Her work has been funded by the American Heart Association, a National Science Foundation CAREER award, a National Heart, Lung, and Blood Institute R01, and the Wu Tsai Foundation. She has been Pulmonary Grand Rounds lecturer at Stanford University Medical Center and a session chair and invited speaker at the Cardiac Physiome Workshop, the ASME Bioengineering Division, SIAM, and the World Congress of Biomechanics among others.
Dr. Valdez-Jasso has been an active mentor for minority students and an advocate for diversity and inclusion at her campuses and for national professional societies. In 2020 she was the campus-wide recipient of the Faculty Inclusion Excellence Award at UC San Diego. At the national level, she is the Chair of the Diversity and Inclusion Committee of the American Society of Mechanical Engineering Bioengineering Division, member of the Bioethics Subcommittee and Strategic Outcomes Subcommittee of the American Heart Association.