Dominique Paderin

Introduction. Heart transplant rejection is caused by the body’s cellular and antibody-mediated immune responses to an allograft.¹The rejection process is associated with swelling and edema, compounding the pathological state. Despite survival rate increases, post-transplantation rejection is a significant cause of mortality.² Targeted lymphangiogenesis via stimulation of VEGFR-3 on LECs by VEGF-C is being explored as a therapeutic mechanism for reducing edema in cardiovascular disease. Methods. After intraperitoneal injections of VEGF-C, lymphatic vascular density(Vv) and length(Lv) were measured in mice subjected to lymph node resection.³ Chronic colitis was induced in mice via oral DSS solution. Vectors containing recombinant VEGF-C genes were injected, and lymphatic vessel density(LVD) measured by immunohistochemical analysis. Lymph drainage was assessed measuring tissue absorbance following Evans blue dye injection.⁴ Another study induced cardiac pressure overload and edema in wildtype and VEGFR-knockdown mice; post-VEGF-C_156S administration, cardiac water content, echocardiography, and histological analysis were performed.⁵ A different study induced MI in rats, followed by intramyocardial administration of slow-release VEGF-C_C152S. Echocardiography measured cardiac function and gross structural change, gravimetry measured cardiac water content, and immunohistochemical analysis measured neolymphangiogenesis.⁶ Intraperitoneally injected VEGF-C_C156S and adenovirus vector(AAV) delivery were compared to determine the most efficacious method. AAV soluble VEGFR-3(sVEGFR-3) was also administered.⁷ Results. Vv and Lv were elevated in treatment groups.³ Significant increases in LVD and lymphatic drainage were similarly recorded(DSS+VEGF-C).⁴ Wildtype mice showed greater reduction in cardiac water content, improvement in contractile function on post-VEGF-C treatment echocardiography, increased levels of neolymphangiogenesis, and reduced hypertrophy.⁵ Following VEGF-C_C152S, increased rates of lymphangiogenesis were observed and associated with improved hemodynamic balance and reduced tissue inflammation.⁶ Only sustained AAV delivery of VEGF-C_C156S produced increased lymphangiogenesis and reduced cardiac inflammation. sVEGFR-3 administration decreased levels of lymphangiogenesis and improved cardiac function.⁷ Conclusion. Elevated Vv and Lv indicated increased volume capacity and lymphatic vessel number following VEGF-C treatment, indicating VEGF-C/VEGFR-3 axis’s ability to increase functional neolymphangiogenesis, reduce inflammation, and edema in chronic colitis– illustrating potential application to edema reduction following heart transplantation.^3,4 Improved cardiac function and reduced pressure overload indicated increased recovery from greater expression of VEGFR-3, pointing to VEGF-C’s ability to reduce sequalae of hypertrophic adaptation.⁵ This suggests VEGF-C_C152S as a therapeutic tool for treating inflammation and edema associated with cardiovascular pathologies, particularly acute heart transplant rejection.⁶ This data contradicts other findings, postulating improved cardiac functioning from reduced T-cell infiltration.⁷ Further research is necessary to solidify the VEGF-C/VEGFR-3 axis as a therapeutic target for reducing edema in cardiac tissues.

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