For all the differences between males and females, here’s one Alison Xie, PhD, wasn’t expecting.
Xie, an assistant professor in the Division of Urology in the University of Colorado Department of Surgery, focuses part of her research on glial cells — cells in the nervous system that help neurons to function — and their role in regulating heart rate and blood pressure. She recently conducted research showing that activating a glial signaling pathway known as GPCR does increase heart rate and blood pressure in animal models. After a few weeks of constant activation, however, blood pressure actually drops below normal — but only in females.
“Long-term hypertension, or elevated blood pressure, in humans can cause the development of cardiovascular disease and eventually heart failure,” Xie says. “Our hypothesis at that time was that if we kept the GPCR pathway activated, the blood pressure would remain high, and eventually we would see the development of heart failure and other effects of hypertension. But to our surprise, what we saw is that when we gave a prolonged activation, we saw hypotension in the female models, which means the blood pressure is significantly lower than where it’s supposed to be.”
Studying sex differences
Xie has received a one-year, $25,000 Early Career Faculty Research Development Award from the Ludeman Family Center for Women’s Health Research on the CU Anschutz Medical Campus to study the issue further, looking for reasons behind the sex difference and to see if the mechanism can be used to develop different ways of targeting males and females with drugs designed to lower blood pressure.
“We’re hoping to identify the signaling pathways in glial cells, because they're a lot easier to target with drugs than neurons, and there are fewer side effects if we target glial cells instead of directly targeting neurons,” she says. “We want to discover how to utilize glial cell signaling to control blood pressure without as many side effects.”
A first step in the research is to extend the period of time in which the GPCR pathway is activated, to see if males eventually develop hypotension as well.
“We’re interested to see whether the males never get this decrease in blood pressure, or if it’s just delayed,” she says. “We’re extending our initial two-week activation period to six weeks, and instead of measuring our progress once a week, we’re doing a constant recording of blood pressure, heart rate, and cardiac output. That way, we’ll be able to say, ‘Did the males catch up to females, and if so, when did that happen? How far apart are they on the curve, and where do they meet?’ That’s one of the goals of this study.”
The role of homeostasis
Xie believes part of the answer lies in the concept of GPCR homeostatic plasticity, which means that when one GPCR signaling pathway is overly or chronically activated, the receptors responsible for activation will be trimmed off in order to normalize the cell.
“This type of thing happens in synaptic transmission all the time,” she says. “Our hypothesis now is that a similar regulation is happening either from glial cells talking to neurons or neurons talking to blood vessels. There may be some plasticity happening in the blood vessels where they say, ‘I can’t be in a state of hypertension all the time. I need to stop listening to those glial cells that are constantly activated.’”
The Ludeman Family Center grant will support the generation of solid preliminary data which will be used to secure a larger grant from the National Institutes of Health to further examine the role of glial cells in blood pressure regulation and study how they might be used to counter the deleterious effects of chronic hypertension.
“Chronic sympathetic activation in humans — if someone’s smoking all the time, if someone’s a type A personality who’s very easily aggravated — their risks of getting hypertension, diabetes, and even kidney disease are much higher than someone who doesn’t smoke or is more relaxed,” Xie says. “There’s a direct link between how active your sympathetic nervous system is and how easily you can get heart failure down the road.”