Hypertension and infertility may not seem to have much in common, but Vanderbilt University Medical Center scientists recently discovered that the same receptor plays a role in both blood pressure control and female fertility.
In a study published this month in Nature Medicine, investigators report that mice lacking the prostaglandin EP2 receptor have salt-sensitive hypertension and reduced fertility. The studies could one-day lead to improved therapies for these two conditions.
The findings also help explain a well-known correlation between non-steroidal anti-inflammatory drug (NSAID) therapy and hypertension.
The work results from the combined efforts of several laboratories, principally those of brothers Richard M. Breyer, Ph.D., associate professor of Medicine and Pharmacology, and Dr. Matthew D. Breyer, associate professor of Medicine and Molecular Physiology and Biophysics.
The EP2 receptor is one of at least four different receptors that cells use to respond to the prostaglandin PGE2. One of the human body's hormonal signals, PGE2 has previously been shown to affect blood pressure. When it is administered intravenously to mice, blood pressure drops.
It was unknown, however, which of its receptors PGE2 uses to reduce blood pressure and to achieve other physiological responses.
In order to address the question of which receptor is important for PGE2 actions, the researchers created mice that do not have any EP2 receptors. They then studied these "EP2 knockout" mice to figure out what the EP2 receptor normally does.
Post-doctoral fellow Dr. Yahua Zhang administered PGE2 intravenously to the mice and measured blood pressure.
"Where PGE2 would normally cause vasodilatation and lowering of blood pressure in the normal mouse, it now causes vasoconstriction and raises blood pressure," Richard Breyer said. "The idea is that there are both dilator and constrictor receptors for PGE2. We've removed one of the dilator receptors and so we unmask a constrictor receptor.
"We then wanted to know if these EP2 knockout mice have changes in their baseline blood pressure. They do, but they are only slightly hypertensive, so we looked to see whether changing the salt content of their diet had an effect on blood pressure."
Dietary salt intake can be an important factor in the magnitude of hypertension in animal models as well as in humans.
"When we put the EP2 knockout mice on a high salt diet, their blood pressure increased dramatically, and it was a very rapid effect," Richard Breyer said.
Why would a high salt diet have this effect?
"We measured PGE2 excretion in the urine and that rose for both normal and knockout mice on the high salt diet. This suggests that something about a high salt diet increases PGE2 production, and in normal mice that serves to dampen the otherwise hypertensive effect of the salt," Matthew Breyer said.
The researchers conclude that since the knockout mice do not have EP2 receptors, they cannot respond appropriately to the increased levels of PGE2. As a result, they develop hypertension.
"Prostaglandin biology may be a contributory factor for salt-sensitive hypertension in human beings. I think our mice will be a nice model for studying this aspect of human hypertension," Richard Breyer said.
Scientists have for some time recognized the correlation between non-steroidal anti-inflammatory drug (NSAID) therapy and hypertension. NSAIDs (like aspirin, acetaminophen, and ibuprofen) are most commonly used in the long-term treatment of arthritis. These drugs block the production of all prostaglandins, including PGE2.
"It has been shown that taking NSAIDs predisposes patients to developing hypertension. This suggests that endogenous prostaglandins play an important role in keeping blood pressure close to normal. When you block prostaglandin production with an NSAID, you remove a predominant dilator prostaglandin and blood pressure goes up. Our work suggests that PGE2 acting through EP2 receptors is an important dilator prostaglandin," Matthew Breyer said.
"It also suggests that different complements of prostaglandin receptors might affect whether a person has hypertension or not. If a person's EP2 receptors were missing or not working, we would expect that person to have hypertension," Richard Breyer said.
There is also evidence that NSAID therapy can lead to temporary infertility in women. The researchers were therefore interested in the fertility of mice lacking the EP2 receptor.
"That was something we didn't really have to look for. The mice told us, because we got reduced litter sizes from the EP2 knockout mice," Richard Breyer said.
Reduced litter size was associated only with the female knockout mice. Post-doctoral fellow Christopher Kennedy, Ph.D., looked at day two of pregnancy and found fewer ovulated eggs and a lower percentage of fertilization in the EP2 knockout mice compared to normal mice.
"It looks like the EP2 receptor knockout affects ovulation as well as fertilization of the egg. I think that's the most surprising finding. We wouldn't have guessed that up front," Richard Breyer said.
Thanks to these studies, the EP2 receptor may serve as a target for new drugs designed for the treatment of hypertension and infertility.
This research started as part of a center grant headed by Dr. John A. Oates, Harvey Branscomb Distinguished Professor and Thomas F. Frist Professor of Medicine. The Breyers also collaborated with Dr. Mark A. Magnuson, professor of Molecular Physiology and Biophysics, and the Transgenic Mouse/ES Cell Shared Resource in creating the genetically altered mice. The work was supported by grants from the NIH.
Journal
Nature Medicine