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Peptides derived from the integrin ? cytoplasmic tails inhibit angiogenesis.
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ABSTRACT: Background
Integrins are essential regulators of angiogenesis. However, the antiangiogenic potential of peptides derived from the integrin cytoplasmic tails (CT) remains mostly undetermined.Methods
Here we designed a panel of membrane-penetrating peptides (termed as m?CTPs), each comprising a C-terminal NxxY motif from one of the conserved integrin ? CTs, and evaluated their antiangiogenic ability using both in vitro and in vivo approaches.Results
We found that m?3CTP, m?5CTP and m?6CTP, derived respectively from the integrin ?3, ?5 and ?6 CTs, but not others, exhibit antiangiogenic ability. Interestingly, we observed that the integrin ?3, ?5 and ?6 CTs but not others are able to interact with ?3-endonexin. In addition, the antiangiogenic core in m?3CTP is identical to a previously identified ?3-endonexin binding region in the integrin ?3 CT, indicating that the antiangiogenic m?CTPs may function via their binding to ?3-endonexin. Consistently, knockdown of endogenous ?3-endonexin in HUVECs significantly suppresses tube formation, suggesting that ?3-endonexin is proangiogenic. However, neither treatment with the antiangiogenic m?CTPs nor knockdown of endogenous ?3-endonexin affects integrin-mediated HUVEC adhesion and migration, indicating that their antiangiogenic effect may not rely on directly regulating integrin activity. Importantly, both treatment with the antiangiogenic m?CTPs and knockdown of endogenous ?3-endonexin in HUVECs inhibit VEGF expression and cell proliferation, thereby providing mechanistic explanations for the functional consequences.Conclusion
Our results suggest that the antiangiogenic m?CTPs can interact with ?3-endonexin in vascular endothelial cells and suppress its function in regulating VEGF expression and cell proliferation, thus disclosing a unique pathway that may be useful for developing novel antiangiogenic strategies.
SUBMITTER: Cao Z
PROVIDER: S-EPMC6029062 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
Peptides derived from the integrin β cytoplasmic tails inhibit angiogenesis.
Cell communication and signaling : CCS 20180703 1
<h4>Background</h4>Integrins are essential regulators of angiogenesis. However, the antiangiogenic potential of peptides derived from the integrin cytoplasmic tails (CT) remains mostly undetermined.<h4>Methods</h4>Here we designed a panel of membrane-penetrating peptides (termed as mβCTPs), each comprising a C-terminal NxxY motif from one of the conserved integrin β CTs, and evaluated their antiangiogenic ability using both in vitro and in vivo approaches.<h4>Results</h4>We found that mβ3CTP, mβ ...[more]
