title: Obese melanocortin-4 receptor-deficient rats exhibit augmented angiogenic balance and vasorelaxation during pregnancy.
abstract: While obesity is a major risk factor for preeclampsia, the mechanisms linking obesity and hypertension during preeclampsia remain unclear. Hypertension in preeclampsia is associated with placental ischemia-induced release of anti-angiogenic soluble fms-like tyrosine kinase (sFlt-1) into the maternal circulation, which antagonizes vascular endothelial growth factor (VEGF) promoting endothelial dysfunction. Haploinsufficiency, defined as loss of one copy of a gene via a mutation, of the melanocortin-4 receptor (MC4R) is the most common cause of monogenetic obesity in humans. The purpose of our study was to determine the effects of genetic obesity on angiogenic balance, endothelial function, and blood pressure in pregnant MC4R+/- and MC4R+/+ rats. At gestational day (GD) 18, body weight and total body fat mass were greater in MC4R+/- than MC4R+/+ rats. On GD 19, plasma sFlt-1 was not significantly different between groups. Interestingly, circulating VEGF was greater in the obese rats with the source being adipose tissue and not the placenta. Wire myography showed in third-order mesenteric arteries that sensitivity (logEC50) to endothelial dependent and nitric oxide donor-induced vasorelaxation was greater in MC4R+/- versus MC4R+/+. Mean arterial blood pressure was similar between groups. In conclusion, under normal pregnant conditions, genetically obese pregnant animals have greater angiogenic balance and dependency of vasorelaxation on nitric oxide signaling protecting against the development of hypertension. However, we speculate that, in the face of reduced uterine perfusion, a rise in circulating placental factors that target and reduce nitric oxide bioavailability exposes the susceptibility of genetically obese animals to greater hypertension in pregnancy.
authors.affiliation: Department of Physiology and Biophysics, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS 39216.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Spradley
authors.forename: Ana C
authors.initials: AC
authors.lastname: Palei
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
keywords: Angiogenic balance; MC4R; blood pressure; obesity; pregnancy; vasorelaxation