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VEGF_164(165) as the Pathological Isoform: Differential Leukocyte and Endothelial Responses through VEGFR1 and VEGFR2

¹From the Massachusetts Eye and Ear Infirmary and ⁴Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts; the ³Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo, Japan; ⁵Imperial Cancer Research, London, United Kingdom; and ⁶Eyetech Research Center, Woburn, Massachusetts.

PURPOSE. Vascular endothelial growth factor (VEGF) induces angiogenesis and vascular permeability and is thought to be operative in several ocular vascular diseases. The VEGF isoforms are highly conserved among species; however, little is known about their differential biological functions in adult tissue. In the current study, the inflammatory potential of two prevalent VEGF isoform splice variants, VEGF_120(121) and VEGF_164(165), was studied in the transparent and avascular adult mouse cornea.

METHODS. Controlled-release pellets containing equimolar amounts of VEGF₁₂₀ and VEGF₁₆₄ were implanted in corneas. The mechanisms underlying this differential response of VEGF isoforms were explored. The response of VEGF in cultured endothelial cells was determined by Western blot analysis. The response of VEGF isoforms in leukocytes was also investigated.

RESULTS. VEGF₁₆₄ was found to be significantly more potent at inducing inflammation. In vivo blockade of VEGF receptor (VEGFR)-1 significantly suppressed VEGF₁₆₄-induced corneal inflammation. In vitro, VEGF₁₆₅ more potently stimulated intracellular adhesion molecule (ICAM)-1 expression on endothelial cells, an effect that was mediated by VEGFR2. VEGF₁₆₄ was also more potent at inducing the chemotaxis of monocytes, an effect that was mediated by VEGFR1. In an immortalized human leukocyte cell line, VEGF₁₆₅ was found to induce tyrosine phosphorylation of VEGFR1 more efficiently.

CONCLUSIONS. Taken together, these data identify VEGF_164(165) as a proinflammatory isoform and identify multiple mechanisms underlying its proinflammatory biology.

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