Catherine Bui

According to a recent Yale co-authored study that was conducted at the Yale School of Medicine, research on smooth muscle cell progenitors could be the key to finding a cure for pulmonary hypertension.

Pulmonary hypertension is a disease in which patients experience high blood pressure in the blood vessels of their lungs. This high blood pressure in the lungs can lead to heart failure in the right side of the heart and ultimate deterioration of patient health, said Daniel Greif, professor of medicine in the cardiology department at the School of Medicine. Yale researchers performed a study on the cardiovascular system of mice and found that a specialized cell known as a “progenitor” is responsible for increasing lung vessels’ blood pressure by making smooth muscle cells in these vessels — a place where smooth muscle cells should not exist. According to the study, pulmonary hypertension can be prevented if the gene that causes the progenitor to become a muscle cell is deleted.

According to Greif, prior research found that during pulmonary hypertension, smaller blood vessels of the lungs — known as arterioles — muscularize, or gain muscle. This muscularization in the arterioles, he said, leads to increased blood pressure in all of the blood vessels of the lung, and eventually leads to pulmonary hypertension.

“One of the key questions [of the Yale study] is where do the excess smooth muscle cells on the distal, small blood vessels come from? How did they get there? What’s controlling that process?” Greif said.

To find the answers to those questions, Abdul Sheikh, a postdoctoral fellow in the department of cardiology at the School of Medicine, turned to mice. He experimented on the cardiovascular systems of mice because they can be genetically manipulated, meaning their genes can be altered and tagged, he said. Sheikh examined the disease while it was living and progressing in the mice subjects, making the mice a very powerful model for studying hypertension, he added.

According to Sheikh, the researchers performed this study by first placing the mice in low oxygen conditions. The low oxygen environment causes the arterioles in the lungs to muscularize in areas where they typically do not have muscle, Sheikh said. They then observed the mice cells’ behavior by tagging them with a fluorescent dye that allowed them to trace the movements of the cells over time. If many cells had moved, there would have been a multitude of colors seen in the arteriole, but only one color dye was found in the arteriole. These results were surprising, Sheik said.

“All the new muscles that [appeared in the arterioles] have the same color. Out of all of these cells, only one is migrating,” Sheikh said.

In the study, the researchers analyzed this single migrating cell and found that it was special — this cell was “primed to muscularize,” Sheikh said. These cells had a signature similar to smooth muscle cells but with an added PDGF-B receptor, he said. When a PDGF-B growth factor is released by another cell, the receptor, which receives the factor, sends a signal for the cell to initiate its migration to the arteriole. This cell, called a smooth muscle cell progenitor, then expresses the gene KLF4. KLF4 causes the cell to continue dividing, creating many new smooth muscle cells in the arteriole, thereby muscularizing the arteriole.

“Now we can think of therapeutic interventions because that is a very important gene. If we delete this gene, perhaps we can stop this muscularization process,” Sheikh said.

Sheikh said that when researchers deleted the KLF4 gene in the progenitor cell in mice models, the cell did not divide. But when the PDGF-B receptor gene was deleted, the progenitor cell did not even migrate to the arteriole — thus, the process of muscularization could never even begin.

About one in four deaths in the United States is due to cardiovascular disorders, including pulmonary hypertension, according to the Centers for Disease Control and Prevention. The CDC also reported that though treatments exist for pulmonary hypertension, no cure exists for the disease.