title: VEGF-C differentially regulates VEGF-A expression in ocular and cancer cells; promotes angiogenesis via RhoA mediated pathway.
abstract: Vascular angiogenesis is regulated by a number of cytokines of which vascular endothelial growth factor (VEGF)-A/and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) play an indisputable role. Similarly lymphangiogenesis is regulated by VEGF-C and its receptor VEGFR3. Currently for treating vasculogenesis diseases such as proliferative retinopathies and cancer, a number of anti-VEGF-A therapies are approved for clinical use. Although clinical efficacies achieved are remarkable, they are found to be transitory in nature, followed by restoration of anti-VEGF therapy resistant angiogenesis. Recently the regulatory role of VEGF-C in initiating and potentiating neo-angiogenesis has been uncovered. Although the interactive nature of VEGF-A and C is known, the dynamics of their expression under knockdown conditions is yet to be established. Here in this study we have utilized siRNA to knockdown both VEGF-A and C either independently or in combination. Analysis of VEGF-A and C expression (only in cancer cell lines MCF7, A549 and H460 but not in the ocular cell line RPE19) has shown enhanced expression levels of VEGF-C with increase in knockdown of VEGF-A. However, VEGF-C knockdown has resulted in decreased expression levels of VEGF-A both in RPE19 and MCF7 cells in a dose dependent manner. In addition, VEGF-C knockdown also resulted in decreased expression of RhoA. Further, knockdown studies of RhoA even with supplementation of VEGF-C or A has resulted in decreased endothelial cell proliferation and stress fiber formation, indicating that VEGF-C does promote angiogenesis via RhoA mediated pathway.
authors.affiliation: Therapeutics Protein Group, Reliance Life Sciences Pvt. Ltd., Dhirubhai Ambani Life Sciences Center, Rabale, Navi Mumbai, Maharashtra, India.
authors.forename: Bharat
authors.initials: B
authors.lastname: Kumar
authors.forename: Shailaja A
authors.initials: SA
authors.lastname: Chile
authors.forename: Kriti B
authors.initials: KB
authors.lastname: Ray
authors.forename: G E C Vidyadhar
authors.initials: GE
authors.lastname: Reddy
authors.forename: Murali K
authors.initials: MK
authors.lastname: Addepalli
authors.forename: A S Manoj
authors.initials: AS
authors.lastname: Kumar
authors.forename: Venkata
authors.initials: V
authors.lastname: Ramana
authors.forename: Vikram
authors.initials: V
authors.lastname: Rajagopal
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005123:Eye / Q000378:metabolism* / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D005136:Eye Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein