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<p>The internalization of vascular endothelial growth factor receptor-2 (VEGFR-2) occurs in response to VEGF treatment, and it is eventually transported to the plasma membrane by several endosomes such as Rab5 and Rab11, which are responsible for transporting vesicles from the cytoplasm to plasma membrane. Therefore, the homeostasis of VEGFR-2 internalization and recycling is critical for maintaining the normality of the VEGF signaling pathway and regulates angiogenesis. Previous studies have shown that discoidin, CUB and LCCL domain containing 2 (DCBLD2) can promote the proliferation and migration of vascular endothelial cells (ECs) by promoting the VEGF signaling pathway, but the potential role of DCBLD2 on VEGFR-2 endocytosis remains unclear. Herein, we found that the deletion of <i>Dcbld2</i> in mice pulmonary microvascular endothelial cells (PMVECs) interfered in progression of VEGFR-2-positive vesicles in cytoplasm returning to the membrane, which functioned by increasing the association of VEGFR-2 with Rab5, while decreasing the association with Rab11. Knockdown of DCBLD2 in human umbilical vein endothelial cells (HUVECs) impaired VEGFR-2 recycling in the same way as that in PMVECs. The deletion of Rab5 in WT PMVECs further attenuated VEGFR-2 signaling induced by VEGF, and overexpression of Rab11 in PMVECs with <i>Dcbld2</i> deletion showed recovery of VEGF-induced signaling. Finally, EC-specific <i>Dcbld2</i> knockout mice showed that DCBLD2 plays a crucial role in promoting angiogenesis. As a receptor-regulating protein, DCBLD2 accelerates the process of VEGFR-2 returning to membrane, which promotes VEGF signaling in ECs and promotes angiogenesis in mice, potentially presenting to be a new therapeutic target for cardiovascular diseases associated with EC damage.</p>

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Discoidin, CUB and LCCL domain containing 2 modulates angiogenesis by inhibiting VEGF receptor 2 endocytosis in endothelial cells

  • 期刊论文

  • 发表日期：

    2025年7月18日

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  • Xiaoning Liu,
  • Shuai Wang,
  • Qi Feng,
  • Chao Yu,
  • Wenjun Zhang,
  • Chenyang Li,
  • Weiwei Yang,
  • Yanhong Zong,
  • Lingling Guo,
  • Runtao Wang,
  • Lijing Li,
  • Yunli Pei,
  • Zihan Song,
  • Honglin Niu,
  • Lei Nie

摘要

The internalization of vascular endothelial growth factor receptor-2 (VEGFR-2) occurs in response to VEGF treatment, and it is eventually transported to the plasma membrane by several endosomes such as Rab5 and Rab11, which are responsible for transporting vesicles from the cytoplasm to plasma membrane. Therefore, the homeostasis of VEGFR-2 internalization and recycling is critical for maintaining the normality of the VEGF signaling pathway and regulates angiogenesis. Previous studies have shown that discoidin, CUB and LCCL domain containing 2 (DCBLD2) can promote the proliferation and migration of vascular endothelial cells (ECs) by promoting the VEGF signaling pathway, but the potential role of DCBLD2 on VEGFR-2 endocytosis remains unclear. Herein, we found that the deletion of Dcbld2 in mice pulmonary microvascular endothelial cells (PMVECs) interfered in progression of VEGFR-2-positive vesicles in cytoplasm returning to the membrane, which functioned by increasing the association of VEGFR-2 with Rab5, while decreasing the association with Rab11. Knockdown of DCBLD2 in human umbilical vein endothelial cells (HUVECs) impaired VEGFR-2 recycling in the same way as that in PMVECs. The deletion of Rab5 in WT PMVECs further attenuated VEGFR-2 signaling induced by VEGF, and overexpression of Rab11 in PMVECs with Dcbld2 deletion showed recovery of VEGF-induced signaling. Finally, EC-specific Dcbld2 knockout mice showed that DCBLD2 plays a crucial role in promoting angiogenesis. As a receptor-regulating protein, DCBLD2 accelerates the process of VEGFR-2 returning to membrane, which promotes VEGF signaling in ECs and promotes angiogenesis in mice, potentially presenting to be a new therapeutic target for cardiovascular diseases associated with EC damage.