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.

血管中的胰岛素信号主要通过典型的 PI3K 和 MAPK 信号通路发挥刺激血管生成和维持血管稳态的作用。然而，血管生成是一个由多个其他信号事件协调的复杂过程。在这里，我们报告了胰岛素受体和内皮糖蛋白/激活素受体样激酶 1 (ALK1) 之间的明显串扰，ALK1 是血管生成所必需的内皮细胞特异性 TGF-β 受体复合物。虽然内皮糖蛋白-ALK1 复合物通常与 TGF-β 或骨形态发生蛋白 9 (BMP9) 结合以通过以下方式促进基因调控转录因子 Smad1/5，我们发现胰岛素驱动胰岛素受体与细胞表面的内皮因子-ALK1 寡聚化，从而触发 Smad1/5 的快速激活。通过定量蛋白质组学分析，我们将 ependymin 相关蛋白 1 (EPDR1) 鉴定为由胰岛素而非 TGF-β 或 BMP9 诱导的主要 Smad1/5 基因靶标。我们发现内皮 EPDR1 表达在基础状态下是最小的，但在延长胰岛素治疗以促进细胞迁移和毛细管形成时显着增强。相反，我们证明 EPDR1 耗竭强烈消除了这些血管生成作用，表明 EPDR1 是胰岛素诱导的血管生成的关键介质。综合起来，