摘要：VEGF信号通路简介（2021-7-25）
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【1】VEGF（血管内皮生长因子）信号通路是VEGF刺激新血管形成的复杂过程。VEGF又称血管通透因子（VPF），是一种二聚体糖蛋白，与细胞表面的VEGF受体（VEGFR）结合，从而激活细胞内酪氨酸激酶，引发一系列涉及血管发生和血管生成的信号级联事件。
◆VEGF 信号通路的功能
【2】VEGF 信号通路在血管生成（vasculogenesis ）和血管新生（ angiogenesis）中起重要作用。血管新生在各种生理和病理疾病中很重要。VEGF 信号通路扮演了对人类有益或有害的双重功能。
【3】一方面，VEGF信号通路的过程有助于骨形成、造血、伤口愈合和发育；另一方面，它促进肿瘤的生长。根据Moses Judah Folkman的肿瘤血管新生（angiogenesis），当肿瘤体积变大时，会诱导新血管的形成来滋养自身并维持其存活。
◆VEGF和VEGFR的分类
【4】在哺乳动物中，VEGF 家族包括 VEGFA、VEGFB、VEGFC、VEGFD、VEGFE 和胎盘生长因子 (PGF)。通常，VEGFA是指VEGF。并且存在三种VEGF受体（VEGFR）：VEGFR-1、VEGFR-2和VEGFR-3。这些受体都属于跨膜酪氨酸激酶受体，包括三个主要区域，即胞外域、跨膜区和胞内羧基末端。现在有很多证据表明 VEGFR-2 是内皮细胞中 VEGF 驱动反应的主要介质。
【5】VEGFA：VEGF通常指的是VEGFA。VEGFA可与VEGFR-1和VEGFR-2结合，促进血管生成，促进内皮细胞迁移和有丝分裂，增加基质金属蛋白酶和αvβ3活性，形成血管腔。
【6】VEGFB：通常，VEGFB 通过与 VEGFR-1 结合来促进胚胎血管生成。
【7】VEGFC：与 VEGFR-2 或 VEGFR-3 结合后，VEGFC 会刺激淋巴管生成。
【8】VEGFD：VEGFD 与 VEGFR-2 或 VEGFR-3 结合以发挥其功能。并且它对于肺细支气管附近的淋巴管系统的发育是必要的。
【9】VEGFE：当它附着在 VEGFR-2 上时，VEGFE 对部分血管生成具有特异性。
【10】PGF：VEGFR-1 的配体之一是 PGF。PGF 对血管生成（vasculogenesis）很重要，它是缺血、炎症、伤口愈合和癌症期间血管生成所必需的。
◆VEGF信号通路的过程
【11】如下图所示，当一个VEGF与其受体结合时，该受体可以瞬时发挥其激酶活性，并与细胞内的酪氨酸或丝氨酸/苏氨酸激酶形成复合物。然后激活的受体导致信号通路中其他蛋白质的激活和各种第二信使的产生。最后，这些信号被传送到细胞核并诱导特定基因的表达，从而调节血管内皮细胞的增殖、存活、迁移和通透性。
【12】VEGF与VEGFR-2结合形成受体二聚体，然后激活PLCγ（磷脂酶Cγ）和PKC-Raf激酶-MEK-丝裂原活化蛋白激酶（MAPK）通路，启动DNA合成促进内皮细胞增殖。同时，Src 信号被激发以启动磷脂酰肌醇 3'-激酶 (PI3K)-Akt 通路，从而增加内皮细胞存活率。Src信号通路的激活也会导致整个基底膜和细胞壁的完全系统性破坏，导致血管通透性增加。CDC42 和 p38 丝裂原活化蛋白激酶 (MAPK) 信号被激发。p38 MAPK 的激活进一步触发肌动蛋白重组并最终引发内皮细胞的迁移。
【解读：VEGFR2后接分别由①PLCγ， ② Src， ③Cdc42连接的信号通路。
通路①：VEGF→VEGFR2→PLCγ→DAG→PKC→SPK→Ras
→Raf-1→MEK→ERK→细胞增殖。
通路②：
VEGF→VEGFR2→Src→PI3K→PIP3→Akt/PKB→Bad→细胞生存。
通路③：
VEGF→VEGFR2→Cdc42→p38→MAPKAPK→HSP27→肌动蛋白重组（actin reorignization）→细胞迁移】
◆与 VEGF 信号通路相关的疾病
【13】VEGF 的过度表达与许多疾病有关，例如实体瘤、乳腺癌、GBM、黑色素瘤和缺氧疾病。当实体瘤长到超过一定的大小时，如果它们的血液供应不足，它们就无法继续生长。然后，肿瘤表达VEGF以促进新血管形成，从而促进自身生长和转移。
◆相关抑制剂
【14】从 VEGF 信号通路的过程可知，VEGF 与 VEGFR 的结合可以启动酶信号级联反应的发生。因此，阻断它们的结合可以有效地终止 VEGF 信号通路。VEGF 抑制剂是一些特定的单克隆抗体，而 VEGFR 抑制剂是一些特定的酪氨酸激酶抑制剂。现有药物如阿柏西普、贝伐珠单抗、ranibizumab和pegaptanib可以抑制 VEGF 并控制或减缓这些疾病。
附：VEGF通路相关示图：
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上图：HCC的相关信号通路及治疗药物[3]
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【解读：上图帮助理解angiogenesis和vasculogenesis】
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【解读：上图可理解雷莫芦单抗作用机制：雷莫芦单抗是一个血管内皮生长因子受体2(VEGFR2)拮抗剂特异性地与VEGF受体2结合和阻断VEGFR配体，VEGF-A，VEGF-C，和VEGF-D与受体的结合。雷莫芦单抗是大分子单抗，进不到细胞内，抑制的是VEGFR2的胞外域。注意雷莫芦单抗与贝伐珠单抗的区别，贝伐珠单抗抑制的是配体VEGF,具体的是VEGFA；雷莫芦单抗抑制的是受体VEGFR2，具体的是VEGFR2的胞外域。】
图17（摘自
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【解读：VEGFR2直接连接的下游信号有6个，① VRAP,② PLCγ, ③ Sck, ④Cdc42, ⑤Src, ⑥PI3K】
There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma;PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling.
目前有大量证据表明VEGFR-2是血管内皮细胞中VEGF驱动反应的主要介导者，在生理和病理血管生成中都被认为是一个重要的信号转导子。VEGF与VEGFR-2的结合导致不同信号通路的级联，导致参与介导内皮细胞增殖和迁移、促进其存活和血管通透性的基因上调。例如，VEGF与VEGFR-2的结合导致受体的二聚化，随后PLCgamma在细胞内被激活；PKC-Raf激酶MEK有丝分裂原激活蛋白激酶（MAPK）通路及随后的DNA合成和细胞生长的启动，而磷脂酰肌醇3'-激酶（PI3K）-Akt通路的激活导致内皮细胞存活率的增加。PI3K、FAK和p38mapk的激活与细胞迁移信号有关。
原文：
VEGF (vascular endothelial growth factor) signaling pathway is a complex process in which VEGF stimulates new blood vessel formation. VEGF, also known as vascular permeability factor (VPF), is a dimer glycoprotein that binds to the VEGF receptor (VEGFR) on the surface of the cells, thereby activating intracellular tyrosine kinase and initiating a series of signaling cascades events involved in vasculogenesis and angiogenesis.
VEGF signaling pathway plays a significant role in vasculogenesis and angiogenesis. Angiogenesis is important in various physiologic and pathologic diseases. VEGF signaling pathway performs a dual function that either beneficial or harmful for humans.
On one hand, the process of the VEGF signaling pathway helps bone formation, hematopoiesis, wound healing and development; on the other hand, it prompts the growth of tumors. According to the tumor angiogenesis of Moses Judah Folkman, when tumor size gets bigger, it will induce the formation of new blood vessels to nourish itself and sustain its existence.
In the mammals, the VEGF family includes VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and placenta growth factor (PGF). Commonly, VEGFA refers to VEGF. And there are three VEGF receptors (VEGFR): VEGFR-1, VEGFR- 2, and VEGFR-3. These receptors all belong to transmembrane tyrosine kinase receptors, including three major regions, namely the extracellular domain, transmembrane region, and intracellular carboxyl-terminal. There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells.
VEGFA: VEGF is usually referred to as VEGFA. VEGFA can bind to VEGFR-1 and VEGFR-2, promoting angiogenesis, facilitating migration and mitosis of endothelial cells, increasing matrix metalloproteinase and αvβ3 activity and creating blood vessel lumen.
VEGFB: Usually, VEGFB prompts embryonic angiogenesis by binding to VEGFR-1.
VEGFC: Upon the combination with VEGFR-2 or VEGFR-3, VEGFC stimulates lymphangiogenesis.
VEGFD: VEGFD binds to VEGFR-2 or VEGFR-3 to exert its function. And it is necessary for the development of lymphatic vasculature nearby lung bronchioles.
VEGFE: VEGFE is specific for partial angiogenesis when it attaches to VEGFR-2.
PGF: One of the ligands for VEGFR-1 is PGF. PGF is important for vasculogenesis, and it is needed for angiogenesis during ischemia, inflammation, wound healing, and cancer.
As shown in the following picture, when a VEGF binds to its receptor, the receptor can transiently exert its kinase activity and form a complex with an intracellular tyrosine or serine/threonine kinase. And then the activated receptors result in the activation of other proteins in the signaling pathway and the production of various second messengers. Finally, these signals are transmitted into the nucleus and induce the expression of specific genes, thereby modulating proliferation, survival, migration, and permeability of vascular endothelial cells.
The binding of VEGF to VEGFR-2 leads to form receptor dimer and then activates the PLCγ (phospholipases C γ) and PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway, which initiates DNA synthesis to promote endothelial cell proliferation. At the same time, Src signaling is provoked to start the activation of the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway, which leads to increased endothelial-cell survival. The activation of the Src signaling pathway will also cause complete systemic destruction of the entire basement membrane and cell wall, resulting in increased vascular permeability. And CDC42 and p38 mitogen-activated protein kinase (MAPK) signaling are incited. Activation of p38 MAPK further triggers actin reorganization and ultimately migration of endothelial cells.
The over-expression of VEGF is contributive to many diseases, such as solid tumors, breast cancer, GBM, melanoma, and hypoxic diseases. When solid tumors grow beyond a limited size, if their blood supply is insufficient, they cannot continue to grow. And then, the tumors express VEGF to promote new blood vessels formation, which facilitates self-growth and metastasis.
As we know from the process of the VEGF signaling pathway, the combination of the VEGF with VEGFR can initiate the occurrence of the enzymatic signaling cascades. Therefore, blocking their binding can effectively terminate the VEGF signaling pathway. VEGF inhibitors are some specific monoclonal antibodies and VEGFR inhibitors are some particular tyrosine kinase inhibitors. Existing drugs such as aflibercept bevacizumab ranibizumab and pegaptanib can inhibit VEGF and control or slow those diseases.
●两种血管生成的经典途径：VEGF信号通路以及血管生成素-TIE2信号转导。
●VEGF是一种肝素结合的同二聚糖蛋白，通过内皮特异性受体酪氨酸激酶/VEGFRs（血管内皮生长因子受体）、VEGFR1（FLT1）、VEGFR2（KDR/Flk1）和VEGFR3（FLT4）发挥作用。VEGF家族的生长因子目前包含其他六个已知的成员，即PLGF（胎盘生长因子）、VEGFA、VEGFB、VEGFC、VEGFD和orf病毒VEGF同源物。
●VEGF是一种分子量大小为40-45kDa的促血管生成因子家族，英文全称Vascular Endothelial Growth Factors。VEGF在1983年被发现的，1989年VEGF蛋白首次被分离，且其在血管生成过程中的作用机制也被发现。
●EGF受体（VEGFR）的结构共有三个部分：细胞外的VEGF结合区，该区域由7个免疫球蛋白样结构构成；受体的跨膜区(TM)；细胞内的信号传导结构域，包括酪氨酸激活结构。
VEGFR和VEGF蛋白结合后，其胞内信号转导区的酪氨酸随即发生磷酸化，从而激活细胞内信号通路，最终导致血管内皮细胞的生长、增殖和成熟，新生血管的生成。
●VEGFR1主要表达于单核细胞和巨噬细胞表面，VEGFR2主要表达于血管内皮细胞表面和相应的胚胎前体细胞，VEGFR3主要表达于淋巴管内皮细胞表面。VEGFA与受体VEGFR2的结合诱导的信号是血管生成的主要控制者。
参考文献：
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[4]血管新生之VEGF信号通路解读【细胞信号通路篇】
原创 管家哥 实验管家 2020-06-19
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