INVESTIGATION OF CELLULAR COMMUNICATIONS IN PROGERIA VASCULATURE

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder in children caused by a point mutation in the lamin A gene, resulting in a toxic form of lamin A called progerin. Accelerated atherosclerosis leading to heart attack and stroke are the major causes of death in these patients. Endothelial cell (EC) dysfunction contributes to the pathogenesis of HGPS-related cardiovascular diseases (CVD). Endothelial cell-cell communications are important in developing the vasculature, and their disruptions contribute to cardiovascular pathology. However, it is unclear how progerin interferes with such communications that lead to vascular dysfunction. An antibody array screening of healthy and HGPS patient EC secretomes identified Angiopoietin-2 (Ang2) as a down-regulated signaling molecule in HGPS ECs. A similar down-regulation of Ang2 mRNA and protein was detected in the aortas from an HGPS mouse model. The addition of Ang2 to HGPS ECs rescues vasculogenesis, normalizes endothelial cell migration and gene expression, and restores nitric oxide bioavailability through eNOS activation. Furthermore, Ang2 addition reverses unfavorable paracrine effects of HGPS ECs on vascular smooth muscle cells. Lastly, by utilizing adenine base editor (ABE)-corrected HGPS ECs and progerin-expressing HUVECs, we demonstrated a negative correlation between progerin and Ang2 expression. Lastly, our results indicated that Ang2 exerts its beneficial effect in ECs through Tie2 receptor binding, activating an Akt-mediated pathway. Together, these results provide molecular insights into EC dysfunction in HGPS and suggest that Ang2 treatment has potential therapeutic effects in HGPS-related CVD. Furthermore, we investigated the role of Yes-associated protein (YAP) in HGPS EC dysfunction, where progerin accumulation disrupts mechanotransduction. We demonstrated that in HGPS ECs, YAP is downregulated, and its nuclear translocation is impaired, leading to reduced expression of Ang2. YAP knockdown in control ECs resulted in tube formation and migration defects, which were rescued by exogenous Ang2 treatment. Our findings highlight a crucial role for YAP in endothelial function and suggest that Ang2 may serve as a therapeutic target to mitigate YAP dysregulation in vascular disorders, such as HGPS.