Possible Target Identified to Prevent Recurrent Blood Vessel Blockages Following Vascular Procedures

The TRPC6 gene plays a role in arterial healing after an injury, according to a new study led by Dr. Graham. This could lead to the development of therapies to reduce the occurrence of intimal hyperplasia and stenosis.

10/21/2020

Researchers from the Department of Biomedical Engineering, led by Linda Graham, MD, have identified that a specific gene, TRPC6, plays a role in preventing arteries from narrowing following injury. The team’s findings, published in the Journal of Vascular Science, suggest that targeting TRPC6 and/or related signaling pathways may be a viable new approach to promote normal healing after arterial damage due to angioplasty or other endovascular procedures.

Here, the researchers compared artery characteristics before and after carotid artery injury between preclinical models that expressed TRPC6 and those genetically engineered to not express the gene.

They found that in models without TRPC6, carotid injury resulted in abnormal artery architecture and stenosis (narrowing of the artery) compared to the genetically normal models.

TRPC6’s effect on contractile biomarkers in smooth muscle cells 

To better understand the gene’s benefit on a mechanistic level, the researchers compared smooth muscle cells cultured from the arteries of preclinical models with and without TRPC6.

The researchers observed that the vascular smooth muscle cells of TRPC6-deficient models had decreased expression of two contractile biomarkers (the proteins SM22 and MYH11), a state that is associated with increased cell proliferation.

“Typically, after a vascular intervention such as angioplasty, smooth muscle cells ‘reprogram’ themselves—that is, dedifferentiate—in order to help the arteries heal,” said Dr. Graham, who is also a practicing vascular surgeon. “This is known as phenotypic switching. Decreased expression of contractile biomarkers and increased cell proliferation, like we saw in our study, are hallmarks of a phenotypic switch.”

TRPC6 helps regulate phenotypic switching, prevent recurrent arterial damage

Dr. Graham went on to explain, however, that dysregulated phenotypic switching can cause intimal hyperplasia and arterial stenosis, as was observed in the TRPC6-deficient preclinical models following injury.

“When we consider our in vitro and in vivo results in tandem, they suggest that TRPC6 expression helps to modulate phenotypic switching, which is widely accepted to be important for facilitating arterial recovery and healing following vascular procedures.”

Based on the team’s findings, future studies will be important to interrogate the time course of TRPC6 expression and/or related signaling pathways following arterial injury in order to identify potential mechanism-based therapies for patients following vascular procedures.

Andrew Smith, MD, is first author on the study, which was supported in part by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. Dr. Smith is a clinical resident in the Department of Vascular Surgery and the first physician to gain admission to the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Molecular Medicine PhD program by way of the Physician Researchers Innovating in Science and Medicine track.

Image: Angioplasty is often combined with the placement of a stent (pictured). The team’s findings suggest targeting TRPC6 will help prevent recurrent blood vessel blockages following endovascular procedures, like angioplasty.



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