Uncovering the Key Mechanism Behind High Blood Pressure

Recent research by the University of Michigan has revealed a crucial biological mechanism that contributes to the development of high blood pressure, or hypertension. Hypertension often involves changes in the structure of blood vessel walls, known as arterial or vascular remodeling, primarily driven by smooth muscle cells in the vessels. The study highlights the role of an enzyme called JMJD3, which influences the expression of endothelin receptors on smooth muscle cells. Endothelin, a potent peptide produced by endothelial cells, binds to these receptors to regulate vessel constriction and dilation. When JMJD3 levels are reduced, as observed in both animal models and human samples, there is an imbalance favoring endothelin receptor-A over receptor-B, leading to decreased vessel relaxation and increased blood pressure.

The researchers demonstrated that diminished JMJD3 expression causes a 'double hit': it elevates endothelin receptor-A expression, promoting vessel constriction, and impairs receptor-B production, which is vital for vessel dilation. This imbalance results in persistent high blood pressure and subsequent arterial remodeling. Further, a common genetic variant, the rs62059712 major T allele, associated with roughly 90% of the population, decreases JMJD3 expression, exacerbating hypertension risk.

In experimental trials, blocking endothelin receptor-A with a specific compound effectively reversed hypertension in mice lacking JMJD3, offering a promising targeted therapy approach. This intervention could be particularly beneficial for individuals harboring the genetic variant that predisposes them to overactive endothelin signaling.

The findings underscore the importance of epigenetic regulation, specifically via JMJD3, in maintaining vascular health and blood pressure homeostasis. They suggest potential for personalized medicine strategies to manage hypertension based on genetic profiling and targeted treatments, ultimately reducing the risk of serious complications like heart attack and stroke.

Published in the Journal of Clinical Investigation, this study advances our understanding of gene-disease interactions in cardiovascular health, paving the way for novel therapeutic options to combat high blood pressure.