Journal
CELL COMMUNICATION AND SIGNALING
Volume 16, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12964-018-0248-8
Keywords
Angiogenesis; Endothelial cells; Integrins; Cytoplasmic tails; beta 3-endonexin
Categories
Funding
- NNSFC [31571177, 31370748, 31500618, 31770967]
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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 beta CTPs), each comprising a C-terminal NxxY motif from one of the conserved integrin beta CTs, and evaluated their antiangiogenic ability using both in vitro and in vivo approaches. Results: We found that m beta 3CTP, m beta 5CTP and m beta 6CTP, derived respectively from the integrin beta 3, beta 5 and beta 6 CTs, but not others, exhibit antiangiogenic ability. Interestingly, we observed that the integrin beta 3, beta 5 and beta 6 CTs but not others are able to interact with beta(3)-endonexin. In addition, the antiangiogenic core in m beta 3CTP is identical to a previously identified beta 3-endonexin binding region in the integrin beta 3 CT, indicating that the antiangiogenic m beta CTPs may function via their binding to beta(3)-endonexin. Consistently, knockdown of endogenous beta(3)-endonexin in HUVECs significantly suppresses tube formation, suggesting that beta(3)-endonexin is proangiogenic. However, neither treatment with the antiangiogenic m beta CTPs nor knockdown of endogenous beta(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 beta CTPs and knockdown of endogenous beta(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 beta CTPs can interact with beta(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.
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