Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis

• DOI: 10.1038/nm.3669
• Publication Date: 2014-09-13T04:12:33Z
• Authors: Jean-Sébastien Joyal; Satra Nim; Tang Zhu; Nicholas Sitaras; José Carlos Rivera; Zhuo Shao; Przemyslaw Sapieha; David Hamel; Melanie Sanchez; Karine Zaniolo; Manon St-Louis; Johanne Ouellette; Martin Montoya-Za...; Alexandra Zabeida; Emilie Picard; Pierre Hardy; Vikrant Bhosle; Daya R Varma; Fernand Gobeil; Christian Beauséjour; Christelle Boileau; William Klein; Morley Hollenberg; Alfredo Ribeiro-d...; Gregor Andelfinger; Sylvain Chemtob
• Keywords: Mice, Knockout; Neurons; Retinal Ganglion Cells; 0303 health sciences; Neovascularization, Pathologic; Sp1 Transcription Factor; Active Transport, Cell Nucleus; Neovascularization, Physiologic; Retinal Vessels; [SDV.BC]Life Sciences [q-bio]/Cellular Biology; Microtubules; Mice, Inbred C57BL; Mice; 03 medical and health sciences; HEK293 Cells; Angiopoietin-1; Animals; Humans; Receptor, PAR-2; Mutant Proteins; Promoter Regions, Genetic; [SDV.BC] Life Sciences [q-bio]/Cellular Biology; Sorting Nexins; Subcellular Fractions

Neurons have an important role in retinal vascular development. Here we show that the G protein-coupled receptor (GPCR) coagulation factor II receptor-like 1 (F2rl1, previously known as Par2) is abundant in retinal ganglion cells and is associated with new blood vessel formation during retinal development and in ischemic retinopathy. After stimulation, F2rl1 in retinal ganglion cells translocates from the plasma membrane to the cell nucleus using a microtubule-dependent shuttle that requires sorting nexin 11 (Snx11). At the nucleus, F2rl1 facilitates recruitment of the transcription factor Sp1 to trigger Vegfa expression and, in turn, neovascularization. In contrast, classical plasma membrane activation of F2rl1 leads to the expression of distinct genes, including Ang1, that are involved in vessel maturation. Mutant versions of F2rl1 that prevent nuclear relocalization but not plasma membrane activation interfere with Vegfa but not Ang1 expression. Complementary angiogenic factors are therefore regulated by the subcellular localization of a receptor (F2rl1) that governs angiogenesis. These findings may have implications for the selectivity of drug actions based on the subcellular distribution of their targets.