The diameter of arteries in healthy individuals is set by how much blood flow they carry, as sensed by the endothelial cells that line the blood vessels. When a tissue grows or becomes more active, endothelial cells in feeder arteries sense the increase in fluid shear stress, the frictional force from blood flow, and activate pathways that induce the artery to enlarge; conversely, if flow decreases, arteries decrease their diameters to match the lower shear stress. In pulmonary hypertension and coronary or peripheral artery disease, pathological factors cause arteries to decrease their diameters, starving downstream tissues of oxygen and nutrients.
A recent study, led by Martin A. Schwartz, PhD, the Robert W. Berliner Professor of Medicine of Cardiology and professor of biomedical engineering and of cell biology and a member of the Yale Cardiovascular Research Center, provides insights on how blood vessels regulate these processes and, in doing so, what goes wrong in disease.
Schwartz and his colleagues found that decreased flow activates the Smad2/3 pathway. This occurs through Alk5, a receptor for the soluble factor BMP9, and neuropilin-1, a receptor shown in other studies to contribute to sensing fluid flow. Activation of Smad2/3 then sets in motion a series of events that result in artery inward remodeling, which restores shear stress to its optimal level and thus shuts off Smad2/3.
While this study focuses on mechanisms of remodeling in healthy arteries, the findings unexpectedly shed light on the pathological inward remodeling in disease that results in tissue ischemia. Smad2/3 can be activated in endothelial cells not through low flow but through inflammatory factors, as occurs in atherosclerosis. Smad2/3 are also activated in pulmonary hypertension.
“We have worked out the pathways that govern physiological artery inward remodeling. In doing so, we have come up with a likely explanation for why arteries close off in patients with artery disease, thus requiring interventions like stents and bypasses,” said Schwartz.
The researchers next hope to gain a better understanding of outward artery remodeling and to explore how these results can be harnessed to prevent restriction of artery diameters in clinical settings.
We have worked out the pathways that govern physiological artery inward remodeling. In doing so, we have come up with a likely explanation for why arteries close off in patients with artery disease.
Martin A. Schwartz, PhD
The study was published Sept. 14 in the Proceedings of the National Academy of Sciences (PNAS).