Sialic acid associated to αvβ3 integrin mediates HIV-1 Tat interaction and endothelial cell proangiogenic activation.

Sialic acid (NeuAc) is a major anion on endothelial cells (ECs)
that regulates different biological processes including angiogenesis.
NeuAc is present in the oligosaccharidic portion of integrins,
receptors that interact with extracellular matrix components,
and growth factors regulating cell adhesion, migration,
and proliferation. Tat is a cationic polypeptide that, once
released by HIV-1 cells, accumulates in the extracellular
matrix, promotingECadhesion and proangiogenic activation by
engaging v3. By using two complementary approaches
(NeuAc removal by neuraminidase or its masking by NeuAcbinding
lectin from Maackia amurensis, MAA), we investigated
the presence of NeuAc on endothelial v3 and its role in Tat
interaction, EC adhesion, and proangiogenic activation. v3
immunoprecipitation with biotinylated MAA or Western blot
analysis of neuraminidase-treated ECs demonstrated that
NeuAc is associated with both the v and the 3 subunits. Surface
plasmon resonance analysis demonstrated that the masking
of v3-associated NeuAc by MAA prevents Tat/v3 interaction.
MAA and neuraminidase prevent v3-dependent EC
adhesion to Tat, the consequent FAK and ERK1/2 phosphorylation,
and EC proliferation, migration, and regeneration in a
wound-healing assay. Finally, MAA inhibits Tat-induced neovascularization
in the ex vivo human artery ring sprouting assay.
The inhibitions are specific because the NeuAc-unrelated lectin
from Ulex europaeus is ineffective on Tat. Also, MAA and
neuraminidase affect only weakly integrin-dependent EC adhesion
and proangiogenic activation by fibronectin. In conclusion,
NeuAc is associated with endothelialv3 and mediates Tat-dependent
EC adhesion and proangiogenic activation. These data
point to the possibility to target integrin glycosylation for the
treatment of angiogenesis/AIDS-associated pathologies.