The long term goal of these studies is to understand the mechanisms by which increased shear stress leads to an enlargement of the maternal uterine circulation during pregnancy. Maternal uterine arteries and veins both widen considerably during pregnancy through a process of structural enlargement termed `expansive' or `outward hypertrophic' remodeling. This is essential for facilitating the many-fold increases in uteroplacental blood flow (UPBF) that are requisite for normal pregnancy outcome. Insufficiency in this remodeling process limits uteroplacental perfusion and is associated with gestational diseases such as early-onset (severe) preeclampsia (PE), and intrauterine growth restriction (IUGR). Although shear stress is a fundamental physiological stimulus for regulating arterial structure, neither the endothelial sensor for this force in the uterine circulation, nor the mechanisms that activate the matrix to induce structural enlargement are understood. Some encouraging but preliminary human data suggest that the normalization of shear stress may be the mechanism that regulates the extent of arterial enlargement. By using a combination of two surgical techniques in rats to alter uterine hemodynamics and restrict pregnancy to one of two uterine horns, we will test the hypothesis that normalization of shear stress is the key mechanism that regulates the extent of uterine arterial remodeling during pregnancy (Aim 1a). We will also determine whether sex steroids ? estrogen in particular ? have permissive or synergistic effects on this process, as suggested by studies in other (non-gestational) settings (Aim 1b). Based on earlier studies that have shown the NO/cGMP signaling pathway to be of primary importance in mediating subsequent changes in arterial structure, the studies in Aim 2 will examine a mechanosensory role for the recently discovered and structurally unique endothelial Piezo1 cation channel in arteries and veins (Aim 2a), and determine whether its activation leads to endothelial NO production and vasodilation, thereby initiating the remodeling process (Aim 2b). Finally, we will examine post-NO signaling of the MT1-MMP/ MMP-2/TIMP2 trimeric enzyme complex to understand how shear stress vs. sex steroids (primarily estrogen) regulate this process.
(Aim 2 c). In sum, these studies will provide new information on the physiological mechanisms that underlie maternal uterine vascular gestational remodeling, a process that is required for facilitating the ten- to twenty-fold increases in uterine blood flow that occur during gestation, and whose attenuation in women is associated with gestational diseases such as preeclampsia and IUGR.
By using a rat model to provoke remodeling by surgically ligating the inflow of blood from the cervical end of the uterus, we will explore the mechanisms by which shear stress is sensed and transduced into increased release of endothelial NO, and examine how post-NO signaling leads to matrix activation and vessel growth. The proposed research is relevant to public health and the NIH mission because it seeks to understand maternal uterine vascular remodeling during pregnancy ? a mechanism that is essential for facilitating the progressive increases in uteroplacental blood flow that are required for normal fetal growth and development.
