Congratulations to Dr. Fenix Araujo, postdoctoral fellow in the Sonkusare lab, on her first-place award at the American Physiological Society Cardiovascular Section Outstanding Postdoctoral Trainee Competition. Fenix presented her work on the non-genomic effects of mineralocorticoid receptors.

Hypertension, high blood pressure, affects approximately half of Americans over the age of 18. Persistent high blood pressure can contribute to heart attack, stroke, vision problems, and kidney disease, making it an important target for pharmaceutical development. “Many patients with high blood pressure are left with treatment-resistant hypertension,” says Araujo. ” There is a critical need to identify new ways of treating hypertension, and this requires a better understanding of pathological mechanisms.”

Blood pressure is controlled in part by smooth muscle cells inside our blood vessels, which can tighten or relax the vessel to control blood flow. “I am working on a fundamentally new mechanism for blood pressure regulation. This mechanism involves a well-known receptor called mineralocorticoid receptor, which alters ion channel activity and regulates smooth muscle contraction,” Araujo explains. To accomplish her objectives, she will use a combination of gene editing techniques, measurements of the electric currents inside cells, and super-resolution microscopy capable of observing individual proteins at the plasma membrane. Running these experiments in model systems and human samples with and without hypertension will allow Araujo to uncover new mechanisms of blood pressure regulation and possibly unlock new treatment options for hypertension.

The AHA Postdoctoral Fellowship is a prestigious, highly competitive award. “It’s an important milestone in my career, and I’m profoundly grateful for the training and support provided by the Sonkusare lab, as well as the research environment at the CVRC,” says Araujo.

Blood vessels are made of concentric layers. Closest to the bloodstream is a layer of endothelial cells, which functions as an internal “skin”, separating flowing blood from the rest of the vessel. These cells become dysfunctional in obesity, contributing to a range of complications. Adjacent to this skin-like layer are smooth muscle cells, which control blood flow and pressure by contracting and relaxing. “When we think about inflammation, we typically focus on immune cells releasing inflammatory signals that affect endothelial or smooth muscle cells,” explains Sonkusare. “We asked a different question: ‘Can endothelial and smooth muscle cells themselves release inflammatory signals that elevate blood pressure?’”

Under healthy conditions, communication between the neighboring endothelial and smooth muscle cells helps maintain a normal blood pressure. Sonkusare’s team hypothesized that this cellular crosstalk becomes disrupted—or even harmful—in obesity. To study the cellular dynamics at play, the Sonkusare Lab fed mice a high-fat diet to develop obesity. They then isolated single cells from small blood vessels of these mice to analyze the inflammatory signals they released. Comparing these samples to those from mice fed a normal diet allowed the lab to identify obesity-dependent changes in inflammatory cell signaling. “We found that in obese mice, smooth muscle cells release the inflammatory molecule TNF, which acts on neighboring endothelial cells,” said Maniselvan Kuppusamy, PhD, first author of the study. Notably, this process occurs only in small arteries that regulate blood pressure—not in large arteries like the aorta. Importantly, the same increase in smooth muscle-derived TNF was observed in small arteries from obese human patients.                

The study further reveals that TNF from smooth muscle cells disrupts a calcium transport protein in endothelial cells, which in turn impairs the blood vessel’s ability to dilate, ultimately increasing blood pressure. Having identified this process, the team sought to disrupt it. The team started with two sets of genetically engineered mice: one set had smooth muscle cells incapable of producing TNF and another with endothelial cells unable to respond to TNF. In both cases, the obese mice showed improved vessel dilation and reduced blood pressure. The team then used a drug that blocks endothelial response to TNF, R7050, in obese mice without genetic modifications. R7050 successfully lowered their blood pressures. Finally, to confirm the clinical significance of their results, the Sonkusare Lab tested R7050 on blood vessels from UVA patients with and without obesity. The drug has beneficial effects in humans as well, opening new research avenues and potential therapies for patients with obesity-related hypertension.

The Sonkusare Lab is currently hiring at the Postdoctoral and Research Scientist levels. Interested parties should contact Sonkusare via email.

My team at UVA focuses on proteins called ion channels. And we study how these ion channels in the vascular wall work together to maintain vascular health —Swapnil Sonkusare, PhD, Professor, Molecular Physiology and Biological Physics

Yen-Lin Chen, PhD, a research scientist in Sonkusare Lab in the Robert M. Berne Cardiovascular Research Center (CVRC), was awarded the NIH Pathway to Independence (K99/R00) Award. This award will support studies of the role of lymph vessel calcium signaling mechanisms in obesity. NIH’s K99/R00 program provides mentored and independent research support for promising postdoctoral scientists. Swapnil Sonkusare, PhD, an associate professor at the CVRC and the Department of Molecular Physiology and Biological Physics, serves as the primary mentor on this grant.

According to the Centers for Disease Control and Prevention reports, nearly 42% of the US population suffers from obesity. Obesity is a major risk factor for heart disease, hypertension, stroke, and diabetes. Emerging evidence points to an important link between disruption of lymph vessel barrier and obesity. Compromised lymph function has also been linked with tissue edema in obesity.

Lymph vessel barrier function is controlled, in part, by calcium signaling mechanisms in the vessel wall. Recent work demonstrates the importance of calcium entry mechanisms in lymph vessel walls in regulating the barrier function of lymph vessels. Dr. Chen’s research will identify the ion channel proteins that enable calcium entry into the lymph vessel wall, their signaling partners, and their contribution to weight gain in obesity. The overall goal is to identify novel calcium signaling mechanisms that maintain the barrier function of lymph vessels and regulate weight gain in obesity.

School of Medicine researchers have identified a key contributor to high blood pressure that could lead to new treatments for a condition which affects almost half of American adults.

The discovery from UVA’s Swapnil Sonkusare, PhD, and colleagues breaks new ground in our understanding of how the body regulates blood pressure. It also shows how problems with this critical biological process drive high blood pressure, also known as hypertension.

“Our work identifies a new mechanism that helps maintain healthy blood pressure and shows how abnormalities in this mechanism can lead to hypertension,” said Sonkusare, of UVA’s Department of Molecular Physiology and Biological Physics and UVA’s Robert M. Berne Cardiovascular Research Center. “The discovery of a new mechanism for elevation of blood pressure could provide therapeutic targets for treating hypertension.”

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