p73 is required for vessel integrity controlling endothelial junctional dynamics through Angiomotin

Abstract

Vascular development comprises vasculogenesis, sprouting and non-sprouting angiogenesis and vessel assembly and remodeling. These processes require the coordinated regulation of intercellular junctions to maintain vascular architecture and vessel barrier. Here we demonstrate a key function for p73 transcription factor orchestrating transcriptional programs involved in the regulation of endothelial cell junction morphology during sprouting angiogenesis. TP73 is required for vessel integrity and stability to maintain the endothelial barrier. p73-downregulation leads to hyperpermeability in vitro, while total-p73 or TAp73-specific knockout results in hemorrhages in vivo. We identified AMOT as a p73 direct transcriptional target. Lack of p73 affects expression, localization, and function of Angiomotin. In turn, stabilization of Angiomotin levels in p73-deficent cells can rescue their junctional defects, altogether demonstrating that AMOT is one of p73-downstream mediators during the regulation of endothelial junction dynamics. These results redefine p73 role in angiogenesis by revealing p73 as a vascular architect that regulates endothelial cell junctions, thereby organizing and stabilizing the endothelial barrier.

Role of angiomotin family members in human diseases (Review)

“…Amot, angiomotin; Amotl1, Amot-like protein 1; Amotl2, Amot-like protein 2; LPTY, LPTY motif; PPEY, PPEY motif; Nedd, neuronal precursor cell-expressed developmentally downregulated; YAP, Yes-associated protein; TAZ, Tafazzin; PALS1, protein associated with Lin seven; Patj, PALS-1-associated tight junction protein; PAR3, partition defective 3; GAP, GTPase-activating protein; ARHGAP17/Rich1, Rho GTPase activating protein 17; MUPP1, multiple PDZ domain protein; Pdlim2, PDZ and LIM domain 2; Syx, Syntaxin; VE-cadherin, vascular endothelial cadherin; TEAD, transcriptional enhanced associate domains; MST1/2, mammalian STE20-like protein kinase 1/2; LATS1/2, large tumor suppressor homolog 1/2; AMP, adenosine 5'-monophosphate; AMPK, AMP-activated protein kinase; Rictor, recombinant protein. TAp73 is a direct transcriptional target of Amot and controls endothelial junction dynamics by regulating angiomotin (48). RICH1 can compete with Merlin for binding to Amot-p80, which activates the kinase cascade of the Hippo signaling pathway and inhibits the stemness of BRCA cells (49).…”

“…Amotl2 is required for aortic lumen dilation and transmits mechanical forces between the endothelial cells by binding to VE-cadherin (73). In addition, TAp73 affects Amot/YAP signaling by integrating the transcriptional program to maintain junction dynamics and integrity and balance endothelial cell rearrangements in angiogenic vessels (48).…”