TY - JOUR
T1 - HtrA3-Mediated Endothelial Cell–Extracellular Matrix Crosstalk Regulates Tip Cell Specification
AU - Guo, Yaru
AU - Ma, Siqin
AU - Xu, Mingming
AU - Wei, Yan
AU - Zhang, Xuehui
AU - Huang, Ying
AU - He, Ying
AU - Heng, Boon Chin
AU - Chen, Lili
AU - Deng, Xuliang
N1 - Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/7/23
Y1 - 2021/7/23
N2 - 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.
AB - 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.
KW - angiogenesis
KW - extracellular matrix
KW - filopodia
KW - HtrA3
KW - tip cell
UR - http://www.scopus.com/inward/record.url?scp=85106325455&partnerID=8YFLogxK
U2 - 10.1002/adfm.202100633
DO - 10.1002/adfm.202100633
M3 - Article
AN - SCOPUS:85106325455
SN - 1616-301X
VL - 31
JO - Advanced Functional Materials
JF - Advanced Functional Materials
IS - 30
M1 - 2100633
ER -