Key mechanism that leads to high blood pressure uncovered microbiologystudy

When someone has high blood pressure, or hypertension, it results in changes to the walls of their blood vessels. This process is known as arterial or vascular remodeling, which is driven by smooth muscle cells in the blood vessel wall. Researchers at Michigan Medicine have uncovered a key mechanism that regulates blood pressure and vascular remodeling—increasing downstream risk of heart attack and stroke—in people with a genetic variant linked to high blood pressure, a study in both animals and human samples suggests.

The results are published in the Journal of Clinical Investigation.

“These findings advance our understanding of gene-disease interactions among a growing list of variants linked to several cardiovascular conditions, such as hypertension,” said Kevin Mangum, M.D., Ph.D., first author and integrated vascular surgery resident at University of Michigan Health.

In the study, investigators analyzed the Jumonji domain-containing protein-3, commonly known as JMJD3, an enzyme that is linked to changes in systolic blood pressure in large genome wide association studies.

The research team found that JMJD3 regulates the expression of the endothelin receptors on the smooth muscle cell.

Endothelin, a chain of amino acids that is produced by endothelial and other cell types, can bind to these receptors on smooth muscle cells to control how much they constrict and dilate.

To investigate JMJD3’s role in hypertension, researchers reduced JMJD3 levels in the smooth muscle cells of mice.

The team found that JMJD3 absence decreased the production of endothelin receptor-B while increasing endothelin receptor-A levels, which limited vessel dilation and raised blood pressure.

“We see that JMJD3 is the key to an intricate balance between the two endothelin receptors that regulate blood pressure,” Mangum said.

Over time, the diminished production of endothelin receptor-B remodeled the blood vessels and raised the risk of hypertension-related complications, such as atherosclerosis and eventual heart attack or stroke, due to increased endothelin receptor-A-mediated signaling.

“A lack of JMJD3 leads to elevations in systolic blood pressure that is mediated by increased endothelin-dependent smooth muscle cell contractility,” he said.

“This occurs in the short term, but the long-term arterial remodeling in hypertension leads to downstream adverse effects on multiple organ systems.”

Investigators then targeted the rs62059712 genetic major T allele variant, which is present in around 90% of people and associated with increased blood pressure.

In both mice and human arterial samples, they found that the major allele genetic variant decreases JMJD3 expression, resulting in a “double hit” increase of both blood pressure and arterial remodeling.

The variant both increases endothelin receptor-A expression, which causes vessels to further constrict, and triggers the downstream remodeling of blood vessels through increased endothelin-ERK signaling in smooth muscle cells within the arterial wall.

When the research team treated mice with a compound, BQ-123, which blocks endothelin receptor A, it reversed hypertension after JMJD3 was deleted.

This potentially offers a targeted therapy for people with the rs62059712 genetic variant to reduce and manage high blood pressure caused by overactive endothelin signaling.

“For this specific population, introducing a personalized therapy to regulate smooth muscle cell plasticity could essentially offset the genetic disadvantage they have that predisposes them to high blood pressure,” said senior author, Katherine Gallagher, M.D., professor of surgery and microbiology and immunology at U-M Medical School and vice chair of basic and translational science in the U-M Health Department of Surgery.

“The strategy we used to determine JMJD3’s role is applicable to a growing list of genetic variants linked to cardiovascular conditions. With so many genetic variants out there, a future focus should be on applications that streamline this process.”