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Wei-Sheng Chen, Zhiyi Cao, Noorjahan A Panjwani; Galectin-8-Induced Angiogenesis Is Independent of VEGF-A But Dependent on Integrins. Invest. Ophthalmol. Vis. Sci. 2017;58(8):998.
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Galectin-8 is a tandem-repeat type galectin that possesses two different carbohydrate-recognition domains. Our recent study has demonstrated that galectin-8 promotes pathological lymphangiogenesis (the growth of lymphatic vessels) through integrins and podoplanin in the absence of vascular endothelial growth factor receptor-3 (VEGFR-3), the major cell surface receptor that drives lymphangiogenesis. In a separate study, galectin-8 has been shown to promote angiogenesis (the growth of blood vessel). However, it is still elusive whether galectin-8-mediated angiogenesis involves VEGF-A/VEGFR-2 signaling axis, the key angiogenic pathway.
Human umbilical vein endothelial cell (HUVEC) sprouting assays, corneal micropocket assays, gene knockdown and antibody blocking assays, and galectin-8 knockout mice were used to assess the role and the mechanism of galectin-8-mediated angiogenesis.
In animal models of suture placement and chemical injury in mouse corneas, we showed that inflammatory angiogenesis is markedly reduced in galectin-8 knockout mice. Further, in the corneal micropocket assay, we demonstrated that galectin-8-induced angiogenesis is not affected by VEGF-A blockage. Similarly, in the in vitro 3D sprouting assay by using HUVEC spheroids, galectin-8-induced HUVEC sprouting is not inhibited by a VEGF-A neutralizing antibody. In contrast, blocking antibodies against specific integrins (α5β1, αvβ3 and αvβ5, but not α9β1) markedly attenuated galectin-8-mediated HUVEC sprouting. Using affinity precipitation assays, we demonstrated that galectin-8-associated integrins (α5, αv, β1, β3 and β5) possess complex N-glycans and α2,6-sialyl glycans but not α2,3-sialyl glycans. Moreover, in the in vitro migration assays, we revealed that immobilized galectin-8 promotes HUVEC migration (haptotaxis), whereas soluble galectin-8 has little effect on HUVEC migration (chemotaxis).
Collectively, our results suggest that galectin-8 functions as an extracellular matrix protein to promote angiogenesis. More importantly, integrins but not VEGF-A/VEGFR-2, play a critical role in galectin-8-mediated angiogenesis.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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