Endothelial YAP1 in Regenerative Lung Growth through the Angiopoietin–Tie2 Pathway

Abstract

Angiogenesis, the formation of new blood capillaries, plays a key role in organ development and regeneration. Inhibition of lung angiogenesis through the blockade of angiogenic signaling pathways impairs compensatory and regenerative lung growth after unilateral pneumonectomy (PNX). The Hippo signaling transducer, Yes-associated protein (YAP1) binds to TEA domain transcription factor (TEAD) and controls organ size and regeneration. However, the role of endothelial YAP1 in lung vascular and alveolar morphogenesis remains unclear. In this report, we have demonstrated that knockdown of YAP1 in endothelial cells (ECs) decreases angiogenic factor receptor Tie2 expression, and inhibits EC sprouting and epithelial cell budding in vitro and vascular and alveolar morphogenesis in the gel implanted on the mouse lung. The expression levels of YAP1, TEAD1, and Tie2 increase in ECs isolated from the remaining mouse lungs after unilateral PNX and vascular formation is stimulated in the post-PNX mouse lungs. Knockdown of endothelial YAP1 inhibits compensatory lung growth and vascular and alveolar morphogenesis after unilateral PNX. These findings suggest that endothelial YAP1 is required for lung vascular and alveolar regeneration and modulation of YAP1 in ECs may be novel interventions for the improvement of lung regeneration.

Role of YAP/TAZ in Cell Lineage Fate Determination and Related Signaling Pathways

“…Furthermore, Choi and Kwon (2015) identified angiopoietin-2 (ANG-2) as a transcriptional target of YAP in regulating the angiogenic sprouting activity of ECs both in vitro and in vivo. Mammoto et al (2019) reported that YAP also regulates the expression of the angiopoietin receptor Tie2.…”

Endothelial Twist1-PDGFB signaling mediates hypoxia-induced proliferation and migration of αSMA-positive cells

“…Endothelial Twist1 mediates hypoxia-induced accumulation of αSMA-positive cells in the gel implanted on the mouse lungs. Blood vessels interact with other cellular and non-cellular components and build complex structures in an organ-specific manner [39][40][41] . Thus, to study vascular structures and cellular interactions in the lung, we developed a system to implant fibrin gel on the lung surface of living mice 12,20,37,41 .…”

“…Blood vessels interact with other cellular and non-cellular components and build complex structures in an organ-specific manner [39][40][41] . Thus, to study vascular structures and cellular interactions in the lung, we developed a system to implant fibrin gel on the lung surface of living mice 12,20,37,41 . To study the effects of hypoxia on PDGFB expression and SMC accumulation in the lung, we implanted fibrin gel supplemented with ECs isolated from B6-GFP mouse lungs (background, C57BL6) on the C57BL6 mouse lung (8-10 week old) for 7 days and treated the mice with hypoxia (8.5%) for the last 3 days 12,37 .…”

Hippo Signaling Pathway as a Central Mediator of Receptors Tyrosine Kinases (RTKs) in Tumorigenesis

“…Moreover, YAP1 knockdown regulates Tie2 expression, such that knocking down YAP1 dramatically decreases Tie2 expression. Lower Tie2 expression blocks angiogenesis and epithelial budding formation in vitro and inhibits compensatory lung growth and vascular formation in vivo [123]. Another study compared YAP/ANG-2 signaling effect on endothelial cell (EC) proliferation in different confluency conditions.…”

“…Reduced MST1/2 phosphorylation by VEGFR and YAP/TAZ effect on VEGFR-induced angiogenesis [118] Effect of actin cytoskeleton dynamics on YAP/TAZ through VEGFR2-SFKs-Rho GTPase [119] Tie (Altiratinib) YAP1/STAT3 complex regulate ANG2 expression promoting angiogenesis [121] YAP-dependent expression of ANG2 is regulated by cellular confluency [122] YAP/TAZ knockdown decreases Tie2 expression and blocks vascular formation [123] FGFR (erdafitinib, Infigratinib) FGF2-SAPK/JNK MAP kinase signaling downregulates TAZ [124] YAP/TBX5 complex controls FGFR1, -2, and -4 expression and FGF5 reduces LATS cellular levels [126] FGF1/FGFR3, MAPK/ERK mediated, increase of ETV5 elevates TAZ activity [127] Different doses of FGF have different effects on hippo and cause distinct outcomes in lens cells [128] FGFR4 mediated breast cancer cell MST1/2 resistance [129] Direct phosphorylation of YAP by FGFR, RET, and MERTK receptors [130] ALK (crizotinib, brigatinib) ALK inhibits LATS and activates YAP to drive tumorigenesis phenotype [132]…”