Abstract 573: Mechanical Stress Alters Cell Signaling and Extracellular Matrix Genes in Fetal Cardiac Valves

Abstract

Objective: Prenatal hypertension leads to mitral annular dilation and is linked to changes in valvular extracellular matrix (ECM) and cell cycle genes including TGFβ-1, BMPs and FGF. We hypothesized that these changes are exacerbated by additional mechanical stress. Methods: Fetal sheep received 8 days of plasma infusion to induce hypertension (HTN, n=5) or lactated ringers solution (CTRL, n=4) starting at 126±2 days gestational age (dGA; term~145 days). Fetal mitral valve interstitial cells (VICs) were isolated at 134±1dGA, cultured in flexible, collagen-coated wells and subjected to 0% (static) or 18% equibiaxial stretch (1 Hz, 24 hrs). mRNA was isolated and qPCR was used to determine the effects of HTN and stretch on gene expression. Statistical analysis was performed via two-way ANOVA with Bonferroni correction. Results: Plasma infusion significantly increased the MAP of HTN fetuses (44.3±2.4 vs 61.6±1.1mmHg, p= 0.002). Change in gene expression is shown in Fig. 1; data are expressed relative to the CTRL/static group. Stretch, but not HTN, significantly increased FGF expression (p<0.05). HTN and stretch each significantly increased expression of TGFβ-1, BMP-1 and -2. Stretch amplified the hypertension-induced increase in these 3 genes (p<0.05 for all). Versican was unaltered by HTN or stretch. Conclusion: Our study demonstrates that early exposure to mechanical stress can shape cell signaling pathway responses in developing fetal cardiac valves, and these changes are amplified when exposed to a secondary stress. These data indicate that the prenatal environment has implications for postnatal cardiac valve function and risk for valvular disease in adulthood.