VEGFR1 and its regulation by thrombin signaling during placental vascular growth

The placenta is a highly vascular organ required to nourish the growing embryo by mediating exchange of nutrients, gases and hormones with maternal blood. The placenta creates a complex vascular network in which fetal endothelial cell-lined blood vessels lie in close proximity to maternal blood. The placenta must grow in concert with the embryo throughout gestation, and defects in placental growth are a common cause of fetal defects as well as maternal cardiovascular diseases such as preeclampsia. The origin and growth of the fetal placental vasculature in the human and mouse placenta are highly conserved, but remain poorly understood at the molecular and genetic levels. Vascular endothelial growth factor (VEGF) and its receptors play essential roles in embryonic development, and VEGFR1 (aka FLT1) is tightly associated with placental dysfunction but distinguish roles of these central vascular regulators in the embryo and placenta has not been possible. To address this gap in knowledge we have used new genetic tools, including Hoxa13-Cre knockin mice that drive gene deletion in endothelial cells of the placenta but not the embryo or yolk sac, and mutant VEGFR1 knockin alleles, to investigate mechanisms of placental vascular growth. Our preliminary studies reveal a central role for VEGFR1 during placental vascular growth, and unexpectedly provide evidence that VEGFR1 may function as an agonist or antagonist during that process. We further find that the signaling by the coagulation protease thrombin regulates placental endothelial VEGFR1 expression, and is required specifically for placental vascular growth. We propose that VEGFR1 and coagulation activity function as key regulators of placental growth that are tightly tied to fetal and maternal complications during pregnancy. We will test this central hypothesis by defining the agonist and antagonist function of VEGFR1 during allantoic vasculogenesis and placental angiogenesis (Aim 1), and by elucidating the organ-specific role of coagulation factor activity and its regulation of VEGFR1 function in the placenta (Aim 2). These studies are expected to yield new insights into the molecular mechanisms of placental vascular growth, the unique role of VEGFR1 receptors in the placenta, and the critical connection between blood clotting and vascular growth in the placenta that is required for successful pregnancy. Project Number: 1R01HL179211-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: MARK KAHN | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $722,824 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CDD-Q (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17921101