Manuel Marin

Introduction. Inhibition of blood flow to the heart can lead to a myocardial infarction (MI)³. This infarcted cardiac tissue promotes release of proinflammatory cytokine pathways that further contribute to cardiomyocyte death². Lymphatic vessels help to maintain cardiac tissue fluid and immune homeostasis. The stimulation of lymphatic growth, or lymphangiogenesis, mediated by VEGF-C, the primary activator of lymphangiogenesis, has been shown to increase lymphatic drainage and reduce inflammation and edema in diseased tissues^4-7. This ability of VEGF-C mediated lymphangiogenesis to promote fluid and immune clearance and assist in restoring cardiac function after a myocardial infarction is tested in this paper. Methods. This study tested implanting lymphatic endothelial progenitor cells (LEPCs) into rat models to study cardiac lymphangiogenesis⁷. Lymphatic endothelial progenitor cells were obtained from the thoracic ducts of Sprague-Dawley rats⁷. The cells were incorporated into a self-assembling peptide (SAP) hydrogel that continuously released VEGF-C⁷. Rat myocardial infarction models were then created by severing the left anterior descending (LAD) coronary artery in 67 rats, with 7 control rats⁷. At 7 days post-transplant, these rats were anesthetized and received cell transplantation⁷. Echocardiograms of the rat hearts were also obtained before the induced MI, 1 week after the induced MI, but before the cell transplant, and 4 weeks after the cell transplant⁷. At 4 weeks transplantation, the rat hearts were harvested and fixed with paraformaldehyde⁷. Results. VEGF-C released from the hydrogel was shown to promote cardiac lymphangiogenesis⁷. Compared with the other groups, there was more myocardium at the infarct region and the scar was decreased greatly in the SAP + LEPCs + VEGF-C group⁷. Ejection fraction and forward stroke were also increased significantly in the SAP + LEPCs + VEGF-C group⁷. At the end of the study, existing cardiac edema was decreased, while angiogenesis and myocardial regeneration were shown to have improved. This treatment combination improved cardiac function post myocardial infarction and presents one possible delivery mechanism for treatment of infarcted myocardium⁷. Conclusions. An important target in the therapeutic use of lymphangiogenesis is the VEGF-C molecule and there is research to show exogenous VEGF-C can improve cardiac function⁹. Therefore, there is a potential treatment in VEGF-C releasing hydrogels combined with LEPC transplantation to improve cardiac function and a potential treatment in using AdVEGF-D^{ΔN ΔC} to treat recurrent angina that is well tolerated^7,11. Consequently, treatment of patients with VEGF-C to promote lymphangiogenesis post myocardial infarction presents a promising new therapy to improve cardiac function.

1. Bhatt AS, Ambrosy AP, Velazquez EJ. Adverse Remodeling and Reverse Remodeling After Myocardial Infarction. Curr Cardiol Rep. 2017 Aug;19(8):71. doi: 10.1007/s11886-017-0876-4.
2. Frangogiannis NG. Pathophysiology of Myocardial Infarction. Compr Physiol. 2015 Sep 20;5(4):1841-75. doi: 10.1002/cphy.c150006.
3. Lu L, Liu M, Sun R, Zheng Y, Zhang P. Myocardial Infarction: Symptoms and Treatments. Cell Biochem Biophys. 2015 Jul;72(3):865-7. doi: 10.1007/s12013-015-0553-4.
4. Yuuki Shimizu, MD, PhD, Rohini Polavarapu, BS, Kattri‐Liis Eskla, BS, Yvanna Pantner, BS, Chad K. Nicholson, MD, Masakazu Ishii, PhD, et al. Impact of Lymphangiogenesis on Cardiac Remodeling After Ischemia and Reperfusion Injury. J Am Heart Assoc. 2018 Oct 2; 7(19): e009565. doi: 10.1161/JAHA.118.009565
5. Kinashi, H., Ito, Y., Sun, T., Katsuno, T., & Takei, Y. Roles of the TGF-β–VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis. Int J Mol Sci. 2018 Aug 23;19(9). pii: E2487. doi: 10.3390/ijms19092487.
6. Yamakawa, M., Doh, S. J., Santosa, S. M., Montana, M., Qin, E. C., Kong, H., … & Chang, J. H. Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies—A review. Med Res Rev. 2018 Sep; 38(6): 1769–1798. doi: 10.1002/med.21496.
7. Zhang, H. F., Wang, Y. L., Tan, Y. Z., Wang, H. J., Tao, P., & Zhou, P. Enhancement of cardiac lymphangiogenesis by transplantation of CD34+ VEGFR-3+ endothelial progenitor cells and sustained release of VEGF-C. Basic Res Cardiol. 2019 Oct 6;114(6):43. doi: 10.1007/s00395-019-0752-z.
8. Huang, Y. W., Tsai, H. C., Wang, S. W., Kuo, S. J., Fong, Y. C., & Tang, C. H. Amphiregulin promotes vascular endothelial growth factor-C expression and lymphangiogenesis through STAT3 activation in human chondrosarcoma cells. Cell Physiol Biochem. 2019;52(1):1-15. doi: 10.33594/000000001.
9. Gancz, D., Raftrey, B. C., Perlmoter, G., Marín-Juez, R., Semo, J., Matsuoka, R. L, et al. Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration. eLife. 2019 Nov 8;8. pii: e44153. doi: 10.7554/eLife.44153.
10. Pan, H. M., Lang, W. Y., Yao, L. J., Wang, Y., & Li, X. L. shRNA-interfering LSD1 inhibits proliferation and invasion of gastric cancer cells via VEGF-C/PI3K/AKT signaling pathway. World J Gastrointest Oncol. 2019 Aug 15; 11(8): 622–633. doi: 10.4251/wjgo.v11.i8.622
11. Hartikainen, J., Hassinen, I., Hedman, A., Kivelä, A., Saraste, A., Knuuti, J., et al. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur Heart J. 2017 Sep 1; 38(33): 2547–2555. doi: 10.1093/eurheartj/ehx352