YAP activation may restore placental blood vessel supply as a therapy for Fetal Growth Restriction

Abstract

The therapeutic potential of YAP activation for Fetal Growth Restriction

Background Therapeutic treatments for Fetal Growth Restriction (FGR) are urgently needed. A primary cause of FGR are placental insufficiencies, often due to poorly developed placental vasculature. We propose a novel therapeutic approach by targeting the Yes Associated Protein (YAP), a growth factor involved in angiogenesis that is downregulated in FGR placentas. This study aims to investigate the therapeutic potential of YAP activation in improving Human Umbilical Vein Endothelial Cell growth (HUVEC), function and blood vessel development in placental tissues.

Methods Human placental explants and HUVECs (n=5/condition) were obtained from normotensive term pregnancies. These were treated with YAP-activating compounds XMU (0.5-5µM), TRULI (0.5-5µM) and TDI (0.001-0.5µM). We confirmed YAP activation and investigated its molecular effects through gene (qPCRs) and protein (Western Blots) analysis. We assessed functional effects of YAP using colorimetric proliferation (0-72hrs) and staining of CD31 (endothelial marker) positive cells in tissues.

Results HUVECs exhibited varying levels of response to the compounds, showing a high degree of patient dependency. TRULI reduces the inactive form of YAP by 42% after 48 hours of treatment, while XMU and TDI show a decrease of 20% and 25% respectively. At 72 hours after treatment, the compounds cause an approximate 20% increase in cell proliferation at the lower doses, compared to vehicle-treated cells. Furthermore, molecular analysis showed that Connective Tissue Growth Factor (CTGF), a downstream target of YAP, was upregulated two-fold on average. These are validated in placental explants treated with the compounds for 24 hours, where there is increased CD31 endothelial cell marker detection.

Conclusion We demonstrate that restoring YAP activity can lead to small but potentially biologically significant increases in proliferation and function. Importantly, our chosen compounds do not appear to deregulate cell growth or death and demonstrates the ability to reverse YAP dysregulation to increase blood vessel endothelial cell proliferation and support angiogenesis.