Obesity affects about 4 in 10 American adults and 1 in 5 children. Beyond excess weight, it triggers internal changes that can lead to serious health problems. One such change is chronic low-level inflammation, which constricts blood vessels and raises blood pressure. Swapnil Sonkusare, PhD, Resident Faculty Member of the Robert M. Berne Cardiovascular Research Center (CVRC) and Professor of Molecular Physiology & Biological Physics, recently led a groundbreaking study published in Circulation Research titled “Paracrine Smooth Muscle-to-Endothelial Signaling via TNF Elevates Blood Pressure in Obesity.” This study identifies a novel inflammatory signaling mechanism that contributes to elevated blood pressure in obesity and highlights the therapeutic potential of targeting this pathway.
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.