Our long-term objective is to unravel the genetics of hypertension. The coming grant is focused on learning how genetic factors influence the consequences of hypertension, with emphasis on uncovering factors affecting the severity of the vascular and renal problems which develop in pre-eclamptic women and in cancer patients under anti-angiogenic therapy who develop microangiopathy (MA). Pre-eclampsia (PE) is a common form of pregnancy-associated hypertension and proteinuria. It accounts for ~15% of maternal deaths, and carries with it a greatly increased risk for future cardiovascular disease. Abnormal increases in the circulating anti-angiogenic factors sFlt1 (a soluble form of the receptor for vascular endothelial growth factor, VEGF) and sEng (a soluble form of co-receptor for tissue growth factor beta, TGF-beta) are associated with PE. Many of the pathological consequences of PE and of MA can be replicated in rodents with recombinant adenoviruses (rAdVs) expressing sFlt1 and/or sEng, and we hypothesize that genetic factors affect the severity of the consequences, and that they are also important in other forms of hypertension. Using novel transgenic mice in which circulating sFlt1 or sEng levels can be increased reversibly by feeding indole-3-carbinol (i3c), a non-toxic dietary supplement, specific aim (i) wil test the hypothesis that the soluble factors affect blood pressure (BP) primarily by increasing systemic vascular resistance. Using novel mice in which endothelin1, (ET1), a factor downstream of sFlt1, and/or TGF?1 expression can be varied globally or tissue-specifically from 10% to 300% of wild type levels, specific aim (ii) will test the hypothesis that modest variations in expression of Edn1 (coding for ET1) and/or Tgfb1 (coding for TGF?1), affect basal BP.
Specific aim (iii) will test the hypothesis that the consequences of exposure to high sFlt1 and sEng are exacerbated or ameliorated by pre-existing genetic factors. The effects of altered expression levels in Edn1, Tgfb1 and Ace will be examined. These experiments are expected to elucidate physiological, pathological and genetic interactions mediating the hypertension and proteinuria induced by sFlt1 and sEng. They have the potential of suggesting new interventions which may be able to postpone or avoid both the need for inducing early parturition in women with severe pre-eclampsia, and the need to discontinue the use of VEGF inhibitors in cancer patients who develop microangiopathy.

Public Health Relevance

Pre-eclampsia (PE) is a form of high blood pressure and kidney problems which occurs in about 1 in every 20 pregnant women in the United States. When PE is severe, the lives of the mother and the baby are at risk, and induced premature delivery is the only certain treatment. Our proposed work will study a replica of the PE mothers'problems in mice, and will use the resulting information to identify possible new treatments to help the mothers and their babies who are exposed to PE.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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OH, Youngsuk
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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