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HtrA3‐Mediated Endothelial Cell–Extracellular Matrix Crosstalk Regulates Tip Cell Specification
Author(s) -
Guo Yaru,
Ma Siqin,
Xu Mingming,
Wei Yan,
Zhang Xuehui,
Huang Ying,
He Ying,
Heng Boon Chin,
Chen Lili,
Deng Xuliang
Publication year - 2021
Publication title -
advanced functional materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.069
H-Index - 322
eISSN - 1616-3028
pISSN - 1616-301X
DOI - 10.1002/adfm.202100633
Subject(s) - angiogenesis , crosstalk , extracellular matrix , microbiology and biotechnology , integrin , pi3k/akt/mtor pathway , cancer research , cell , biomedical engineering , biology , signal transduction , medicine , engineering , biochemistry , electronic engineering
Angiogenesis is critical in tissue engineering and regenerative medicine. Once initiated, outgrowing capillaries are spearheaded by specialized endothelial cells (ECs) termed tip cells. Specification of tip cells from ECs during angiogenesis is greatly influenced by the surrounding extracellular matrix (ECM). However, the crosstalk between ECs and the ECM in tip cell specification is poorly understood. Here, this study shows that the high‐temperature requirement A3 (HtrA3) protein is deeply involved in this process. Specifically, HtrA3 is upregulated in the frontal area of tissue repair and cancer progression through VEGFR2 activation by VEGF in ECs. Secreted HtrA3 degrades the surrounding Collagen IV, which provides space for tip cell morphogenesis and exposes integrin β1‐related ligands. Integrin β1‐ligand binding activates PI3K/AKT/mTOR signaling, which subsequently suppresses the Notch signaling pathway, eventually promoting tip cell specification. Moreover, local administration of exogeneous recombinant HtrA3 in rat cranial bone defects significantly increases blood vessel formation. Conversely, injection of HtrA3 siRNA decreases developmental retinal angiogenesis. These data show that HtrA3 mediated crosstalk between ECs and the ECM enhances tip cell specification of ECs. Hence, HtrA3 can act as a therapeutic agent for improving angiogenesis in situations in need, as well as serve as a therapeutic target for pathological angiogenesis.