Many people with obesity also develop high blood pressure, but the mechanism that leads to this remains unclear. A new study using human tissue samples and mouse models may now have found an explanation.
Obesity is a top risk factor for elevated blood pressure, though researchers remain unsure as to the exact mechanisms underlying this relationship.
Past research has suggested that to find the mechanism that mediates the relationship between obesity and high blood pressure, scientists should look to the endothelium — that is, the cells that line the insides of blood vessels.
In a new study, researchers from the University of Virginia School of Medicine in Charlottesville have done precisely that. They turned their attention to the endothelium to try to find out exactly how obesity can lead to high blood pressure.
To do so, they studied potential mechanisms in human tissue samples and in mouse models.
They report their findings in a study paper in the journal Circulation.
How calcium signaling becomes impaired
In their study paper, the investigators explain that to regulate blood flow, vessels dilate and contract as appropriate. This happens due to calcium signaling: Calcium ions communicate with cells, regulating vasodilation by effectively telling the vessels when to dilate.
In obesity, however, calcium signaling within blood vessels appears to be impaired. This affects vasodilation and contributes to high blood pressure.
Yet the mechanism underlying this impairment remains unclear. To learn more about the specific causes behind high blood pressure in obesity, the researchers investigated cellular mechanisms in human tissue samples and mice — under both normal conditions and those that induce obesity.
They found that, normally, a protein called TRPV4 — which is present on the membranes of endothelial cells — allows calcium ions to enter the cells and maintain normal blood pressure.
However, the researchers also found that in obesity, this protein stops “doing its job” — but only in myoendothelial projections, which are specialized extensions of the endothelial cells.
“Under healthy conditions, TRPV4 at these tiny microdomains [the myoendothelial projections] helps maintain normal blood pressure,” explains lead study author Swapnil Sonkusare, Ph.D.
However, when not everything works as it should, these key entry points for calcium become what Sonkusare terms “pathological microdomains.”
“We, for the first time, show the sequence of events that lead to a harmful microenvironment for calcium entry through TRPV4,” he explains.
“I think the concept of pathological microdomains is going to be very important, not just for obesity-related studies but for studies of other cardiovascular disorders as well,” he adds.
Opening a door to better treatments
According to Sonkusare and team, in obesity, the segments of endothelial cells that hold TRPV4 exhibit an increase in the levels of enzymes that produce peroxynitrite.
This is an ion that silences TRPV4, stopping calcium from entering the epithelial cells. This, in turn, leads to poorer regulation of blood pressure, potentially causing it to become elevated.
Based on this information, researchers may one day be able to come up with a drug that targets this mechanism. Which part of the mechanism should they aim to target, however?
“People asked me, ‘Why don’t you use a drug to directly activate TRPV4?’” says Sonkusare. “But TRPV4,” he explains, “is present in many other tissues, including brain, muscle, and bladder.”
“So if you directly activate TRPV4, you will likely get undesirable side effects.” According to Sonkusare, that is why “[t]he better approach would be to target the specific events that reduce TRPV4 function in obesity.”
In this case, he says, it may be helpful to act directly on either peroxynitrite or the enzymes that produce it. This approach might help regulate blood pressure without causing unwanted effects.
“We, for the first time, identify peroxynitrite as the precise oxidant molecule that increases blood pressure in obesity. The next step would be to design drugs that specifically target peroxynitrite and provide therapeutic benefit,” he explains.
The researchers also note that their recent findings were possible due to the use of innovative, sophisticated techniques that allow real-time visualization of calcium and TRPV4 interactions in very small blood vessels.
Sonkusare concludes: “Historically, researchers have studied larger blood vessels that don’t control blood pressure. Because of our unique techniques, we are able to study the microdomains in very small arteries that control the blood pressure. So our technical ability allows us to obtain these unique insights.”