Ion channel puts the squeeze on blood vessels, affecting blood pressure
by Charlotte Schubert
Blood pressure is exquisitely regulated to respond to our physiological state. Stress raises blood pressure. Simply stand up, and the arteries constrict to maintain pressure.
New findings in mice show how a protein called PKD2 helps regulate blood pressure by mediating such constriction via the smooth muscle cells that envelop arteries. Simon Bulley et al. show that PKD2 acts as a channel to admit sodium into the smooth muscle cells, resulting in vasoconstriction. The findings, recently published in eLife, also suggest that PKD2 may have a role in hypertension, a state of elevated blood pressure that contributes to the deaths of 1,000 people each day in the United States.
PKD2, also called Transient Receptor Potential Polycystin 1 (TRPP1), belongs the TRP family of ion channels. About a dozen members of the TRP family are proposed to be expressed in smooth muscle cells in mammals, but their exact roles are unclear.
To take a look at PKD2, Bulley et al. induced the knockout of PKD2 specifically in smooth muscle cells of specially engineered adult mice. The researchers found that, compared with normal mice, these knockout mice had lower blood pressure and had less severe hypertension when researchers induced the condition with a drug.
The researchers went further, isolating blood vessels and deploying electrophysiological studies in the smooth muscle cells of normal arteries. They showed that PKD2 operates primarily as a sodium channel at the plasma membrane of smooth muscle cells. When activated, PKD2 enables sodium to flow into the cell, promoting a cascade of events that prompt calcium influx into the cytoplasm — the result is constriction of smooth muscle cells. When the smooth muscle cells in arteries constrict, artery diameter decreases, raising blood pressure.
The researchers found that PKD2 responded to different stimuli in the arteries of different organs of the mouse. In the arteries in the small intestine, PKD2 responded to activation of alpha1-andrenergic receptors, which conveys signals from norepinephrine, a vasoconstrictor in the circulation. In the arteries of skeletal muscle, PKD2 responded to increased pressure within the vasculature, which occurs, for instance, when blood flows into arteries during physical activity.
“What these data suggest is that PKD2 channels are activated by different stimuli in different vascular beds,” says lead study author Jonathan Jaggar, a professor in the Department of Physiology at the University of Tennessee in Memphis. “People are beginning to accept that not all arteries are the same.” Jaggar and his colleagues also found additional PKD2-hypertension links — for instance showing that PKD2 expression was increased on the cell surface of smooth muscle cells in a mouse model of hypertension.
The new study is a “technical tour de force,” that deploys a range of methods, says Christopher Garland, a professor of Vascular Pharmacology at Oxford University, who was not involved in the study. He adds that the data are “convincing.” However, Garland notes that blood pressure regulation and hypertension involves multiple cell types, molecular pathways and systems in the body. As with many studies in the field, the question becomes “how to fit it into the bigger picture,” he says. “And the bigger picture is pretty complicated.”
For instance, researchers want to know how PKD2 interacts with other molecular regulators involved in blood pressure. And it’s unclear whether PKD2 may have a similar role in other species such as humans, which are hard to study in part because healthy human blood vessels are not readily available.
The study hints that PKD2 could be a new potential target for the development of new, badly-needed therapies for hypertension. But much more research will be necessary, particularly since PKD2 is found in different cell types throughout the body and may have multiple functions. For instance, PKD2 is a gene mutated in many people with the common genetic disorder Autosomal Dominant Polycystic Kidney Disease (ADPKD).
Curiously, ADPKD patients often have hypertension prior to onset of kidney dysfunction. Jaggar would like to study how PKD2 mutations associated with the kidney disorder affect blood pressure — for instance by examining mice that have the same mutations in PKD2.
Originally published at blog.pnas.org on December 15, 2018.
