EPDR1 is a noncanonical effector of insulin-mediated angiogenesis regulated by an endothelial-specific TGF-β receptor complex.

TitleEPDR1 is a noncanonical effector of insulin-mediated angiogenesis regulated by an endothelial-specific TGF-β receptor complex.
Publication TypeJournal Article
Year of Publication2022
AuthorsAhmed T, Flores PCruz, Pan CC, Ortiz HR, Lee YS, Langlais PR, Mythreye K, Lee NY
JournalJ Biol Chem
Date Published2022 Sep
KeywordsActivin Receptors, Type II, Animals, Chlorocebus aethiops, COS Cells, Endoglin, Growth Differentiation Factor 2, Humans, Insulin, Mice, Neovascularization, Pathologic, Nerve Tissue Proteins, Phosphatidylinositol 3-Kinases, Proteomics, Receptor, Insulin, Receptors, Transforming Growth Factor beta, Smad1 Protein, Smad5 Protein, Transforming Growth Factor beta

Insulin signaling in blood vessels primarily functions to stimulate angiogenesis and maintain vascular homeostasis through the canonical PI3K and MAPK signaling pathways. However, angiogenesis is a complex process coordinated by multiple other signaling events. Here, we report a distinct crosstalk between the insulin receptor and endoglin/activin receptor-like kinase 1 (ALK1), an endothelial cell-specific TGF-β receptor complex essential for angiogenesis. While the endoglin-ALK1 complex normally binds to TGF-β or bone morphogenetic protein 9 (BMP9) to promote gene regulation via transcription factors Smad1/5, we show that insulin drives insulin receptor oligomerization with endoglin-ALK1 at the cell surface to trigger rapid Smad1/5 activation. Through quantitative proteomic analysis, we identify ependymin-related protein 1 (EPDR1) as a major Smad1/5 gene target induced by insulin but not by TGF-β or BMP9. We found endothelial EPDR1 expression is minimal at the basal state but is markedly enhanced upon prolonged insulin treatment to promote cell migration and formation of capillary tubules. Conversely, we demonstrate EPDR1 depletion strongly abrogates these angiogenic effects, indicating that EPDR1 is a crucial mediator of insulin-induced angiogenesis. Taken together, these results suggest important therapeutic implications for EPDR1 and the TGF-β pathways in pathologic angiogenesis during hyperinsulinemia and insulin resistance.

Alternate JournalJ Biol Chem
PubMed ID35872017
PubMed Central IDPMC9396412
Grant ListP30 CA023074 / CA / NCI NIH HHS / United States
R01 CA219495 / CA / NCI NIH HHS / United States
R01 GM128055 / GM / NIGMS NIH HHS / United States
Faculty Member Reference: 
Nam Lee, Ph.D.