Vascular endothelial growth factor A (VEGFA), which plays a key role in angiogenesis, is composed of many isoforms. Distinct VEGFA isoforms are generated by alternative splicing of VEGFA mRNA and named as VEGFxxx, where xxx represents the number of amino acids present in the final protein sequence. These isoforms have opponent pro- and antiangiogenic effects. VEGF-Ax, an additional isoform containing a 22-amino-acid extension in the COOH terminus, arising from VEGFA mRNA, programmed translational readthrough. The function of VEGF-Ax is not clear, especially the conclusion that VEGF-Ax regulates angiogenesis is contradictory. Thus, we investigated the effect of VEGF-Ax on differentiation and angiogenesis of rat bone marrow mesenchymal stem cells (BMMSCs). The results showed that VEGF-Ax could promote the proliferation and migration of BMMSCs, stimulate the differentiation of BMMSCs into endothelial cell-like cells, and protect BMMSCs from endoplasmic reticulum stress-induced apoptosis.
Get full access to this article
View all access options for this article.
References
1.
JohnsonKE and WilgusTA. (2014). Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care, 3:647–661.
2.
LaiTH, VlahosN, Shih IeM and ZhaoY. (2015). Expression patterns of VEGF and Flk-1 in human endometrium during the menstrual cycle. J Reprod Infertil, 16:3–9.
3.
AlkimC, AlkimH, KoksalAR, BogaS and SenI. (2015). Angiogenesis in inflammatory bowel disease. Int J Inflamm, 2015:970890.
4.
VedN, HulseRP, BestallSM, DonaldsonLF, BainbridgeJW and BatesDO. (2017). Vascular endothelial growth factor-A165b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina. Clin Sci, 131:1225–1243.
5.
SajibS, ZahraFT, LionakisMS, GermanNA and MikelisCM. (2018). Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis, 21:1–14.
6.
ApteRS, ChenDS and FerraraN. (2019). VEGF in signaling and disease: beyond discovery and development. Cell, 176:1248–1264.
7.
YeX, Abou-RayyahY, BischoffJ, RitchieA, SebireNJ, WattsP, ChurchillAJ and BatesDO. (2016). Altered ratios of pro- and anti-angiogenic VEGF-A variants and pericyte expression of DLL4 disrupt vascular maturation in infantile haemangioma. J Pathol, 239:139–151.
8.
RamjiawanRR, GriffioenAW and DudaDG. (2017). Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy?. Angiogenesis, 20:185–204.
9.
PaineSK, MondalLK, BorahPK, BhattacharyaCK and MahantaJ. (2017). Pro- and antiangiogenic VEGF and its receptor status for the severity of diabetic retinopathy. Mol Vision, 23:356–363.
XinH, ZhongC, NudlemanE and FerraraN. (2016). Evidence for pro-angiogenic functions of VEGF-Ax. Cell, 167:275–284. e276.
12.
PytelD, SeybK, LiuM, RaySS, ConcannonJ, HuangM, CunyGD, DiehlJA and GlicksmanMA. (2014). Enzymatic characterization of ER stress-dependent kinase, PERK, and development of a high-throughput assay for identification of PERK inhibitors. J Biomol Screen, 19:1024–1034.
13.
WalterP and RonD. (2011). The unfolded protein response: from stress pathway to homeostatic regulation. Science, 334:1081–1086.
14.
PytelD, MajsterekI and DiehlJA. (2016). Tumor progression and the different faces of the PERK kinase. Oncogene, 35:1207–1215.
15.
VandewynckelYP, LaukensD, GeertsA, BogaertsE, ParidaensA, VerhelstX, JanssensS, HeindryckxF and Van VlierbergheH. (2013). The paradox of the unfolded protein response in cancer. Anticancer Res, 33:4683–4694.
16.
YanB, LiuS, LiX, ZhongY, TongF and YangS. (2019). Preconditioning with endoplasmic reticulum stress alleviated heart ischemia/reperfusion injury via modulating IRE1/ATF6/RACK1/PERK and PGC-1alpha in diabetes mellitus. Biomed Pharmacother, 118:109407.
17.
MollereauB, ManieS and NapoletanoF. (2014). Getting the better of ER stress. J Cell Commun Signal, 8:311–321.
18.
ParkJH, KimM and OhJH. (2017). Effects of bevacizumab on endoplasmic reticulum stress in hypoxic retinal pigment epithelial cells. PLoS One, 12:e0179048.
19.
DuanQ, NiL, WangP, ChenC, YangL, MaB, GongW, CaiZ, ZouMH and WangDW. (2016). Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo. Aging Cell, 15:625–633.
20.
MatsuiA, KanekoH, KachiS, YeF, HwangSJ, TakayamaK, NagasakaY, SugitaT and TerasakiH. (2015). Expression of vascular endothelial growth factor by retinal pigment epithelial cells induced by amyloid-beta is depressed by an endoplasmic reticulum stress inhibitor. Ophthalmic Res, 55:37–44.
21.
BinetF and SapiehaP. (2015). ER stress and angiogenesis. Cell Metab, 22:560–575.
22.
ZouJ, FeiQ, XiaoH, WangH, LiuK, LiuM, ZhangH, XiaoX, WangK and WangN. (2019). VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy. J Cell Physiol, 234:17690–17703.
WuS, ZhuX, GuoB, ZhengT, RenJ, ZengW, ChenX and KeM. (2019). Unfolded protein response pathways correlatively modulate endoplasmic reticulum stress responses in rat retinal muller cells. J Ophthalmol, 2019:9028483.
26.
LiJ, WangD, LiuJ, QinY, HuangL, ZengQ, XiaoM, HuJ, YangQ, et al. (2017). Rce1 expression in renal cell carcinoma and its regulatory effect on 786-O cell apoptosis through endoplasmic reticulum stress. Acta Biochim Biophys Sin, 49:254–261.
27.
DjordjevicS and DriscollPC. (2013). Targeting VEGF signalling via the neuropilin co-receptor. Drug Discov Today, 18:447–455.
28.
GuoHF and Vander KooiCW. (2015). Neuropilin functions as an essential cell surface receptor. J Biol Chem, 290:29120–29126.
29.
PeachCJ, MignoneVW, ArrudaMA, AlcobiaDC, HillSJ, KilpatrickLE and WoolardJ. (2018). Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2. Int J Mol Sci, 19(4):pii:E1264. DOI: 10.3390/ijms19041264.
30.
FerraraN and AdamisAP. (2016). Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov, 15:385–403.
31.
SimonsM, GordonE and Claesson-WelshL. (2016). Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol, 17:611–625.
32.
LanahanA, ZhangX, FantinA, ZhuangZ, Rivera-MolinaF, SpeichingerK, PrahstC, ZhangJ, WangY, et al. (2013). The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev Cell, 25:156–168.
33.
CatenaR, LarzabalL, LarrayozM, MolinaE, HermidaJ, AgorretaJ, MontesR, PioR, MontuengaLM and CalvoA. (2010). VEGF(1)(2)(1)b and VEGF(1)(6)(5)b are weakly angiogenic isoforms of VEGF-A. Mol Cancer, 9:320.
34.
EswarappaSM and FoxPL. (2015). Antiangiogenic VEGF-Ax: a new participant in tumor angiogenesis. Cancer Res, 75:2765–2769.
35.
SalminenA, KauppinenA, HyttinenJM, ToropainenE and KaarnirantaK. (2010). Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization. Mol Med, 16:535–542.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
