During pregnancy, uteroplacental blood flow increases many-fold in every mammalian species (including the human). This physiological process is accomplished by the coordinated growth and remodeling of the entire maternal uterine circulation and the creation of a new fetal vascular organ - the placenta. The clinical relevance of maternal gestational uterine vascular adaptation is underscored by the fact that uteroplacental underperfusion is causally linked to several major gestational diseases such as preeclampsia and IUGR. Notably, there is no cure for either condition, and the only available treatment options are palliative; hence, understanding the mechanisms that regulate expansive uterine artery remodeling is essential for developing targeted therapies aimed at improving uteroplacental perfusion. The proposed studies are designed to test the hypothesis that venoarterial signaling (VAS: the passage of placentally-derived pro-angiogenic and vasoactive molecules from veins to adjacent arteries) is an important underlying physiological mechanism for regulating arterial remodeling and tone. The studies in Aim 1 will use two novel surgical approaches - selective ligation (Aim 1a) and venous encirclement with a pliable teflon film (Aim 1b) - and take advantage of the vascular architecture and hemodynamics of the rodent uterine circulation to alter inflow and shear stress so as to differentiate the relative contribution of eah mechanism to arterial remodeling (Aim 1c). The studies in Aim 2 will extend these findings by characterizing the molecular weight dependency of the signaling process (Aim 2a) and by testing the hypothesis that intravenous-derived vasoactive molecules (phenylephrine, VEGF) have the capacity to modulate arterial tone (Aim 2b). At the completion of this project, we will have confirmed or refuted the existence of this intriguing and novel vascular mechanism with regard to gestational uterine arterial remodeling, and will have begun to characterize the dynamics and functional consequences (changes in arterial structure and tone) of venoarterial signal transfer.
This project will establish whether venoarterial signaling (VAS) - the passage of placentally-derived growth-promoting and vasoactive signals from vein to artery - is a credible mechanism for regulating uterine arterial tone and remodeling. Clinical importance derives from the fact that placental underperfusion is causal to preeclampsia and IUGR. Therefore, understanding the mechanisms that regulate arterial expansive remodeling (the process that facilitates the dramatic increases in uterine blood flow that are both characteristic of mammalian gestation, and requisite for normal pregnancy outcome) is an essential step toward developing novel therapeutic strategies for ameliorating the development of gestational vascular diseases.
