A genetic cause for hypertension during pregnancy

Blood pressure normally dips slightly during pregnancy but, as every obstetrician knows, a spike in pressure can lead to a serious and potentially life-threatening complication. The reasons for this type of hypertension, which occurs in about 6 percent of pregnancies, remain mysterious but research by a Yale team has shed the first light on a likely molecular cause.

Working with a family predisposed to a rare form of hypertension, David Geller, M.D., Ph.D., and colleagues identified a mutation in a protein in kidney cells that normally regulates salt balance. The protein, known as the mineralocorticoid receptor, is normally activated by the steroid aldosterone. The Yale scientists found that, in patients with the mutation, it is also activated by the hormone progesterone. “The consequence is that when women with this mutation become pregnant, the 100-fold rise in progesterone levels activates the receptor, causing increased salt balance and a marked increase in blood pressure,” said the paper’s senior author, Richard P. Lifton, M.D., Ph.D., a Howard Hughes Medical Institute (HHMI) investigator and professor of genetics, medicine, and molecular biophysics and biochemistry. Hypertension during pregnancy can lead to preeclampsia, which may be fatal to mother, fetus or both. The team’s findings were reported in the July 7 issue of Science.

“Our findings demonstrate that a normal hormone of pregnancy can have abnormal effects that can cause hypertension to worsen. This raises the possibility that more common forms of pregnancy-related hypertension may be attributable to similar mechanisms,” Lifton said. This information, he said, will motivate careful examination of the possibility that progesterone is acting to promote increased salt balance in other forms of pregnancy-related hypertension and may lead to clinical trials of salt restriction in selected groups of women whose blood pressure rises with pregnancy.

The paper was dedicated to the memory of the late Paul B. Sigler, M.D., who died in January 2000. Sigler, a noted Yale and HHMI structural biologist, created a computer model of the mineralocorticoid receptor and demonstrated how the mutated receptor might be activated by progesterone. The group then used this model to perform further experiments that proved the mechanism of action of the mutation.