C3G promotes a selective release of angiogenic factors from activated mouse platelets to regulate angiogenesis and tumor metastasis
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Víctor Martín-Granado1,2, Sara Ortiz-Rivero1,2, Rita Carmona3, Sara Gutiérrez-Herrero1,2, Mario Barrera1, Laura San-Segundo1,2, Celia Sequera4, Pedro Perdiguero2,5, Francisco Lozano2,6, Francisco Martín-Herrero2,5, José Ramón González-Porras2,7, Ramón Muñoz-Chápuli3, Almudena Porras4 and Carmen Guerrero1,2,8
1Instituto de Biología Molecular y Celular del Cáncer, USAL-CSIC, Salamanca, Spain
2Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
3Departamento de Biología Animal, Universidad de Málaga, Málaga, Spain
4Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
5Departamento de Cardiología, Hospital Universitario de Salamanca, Universidad de Salamanca, Salamanca, Spain
6Departamento de Angiología y Cirugía Vascular, Hospital Universitario de Salamanca, Universidad de Salamanca, Salamanca, Spain
7Departamento de Hematología, Hospital Universitario de Salamanca, Universidad de Salamanca, Salamanca, Spain
8Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
Carmen Guerrero, email: firstname.lastname@example.org
Almudena Porras, email: email@example.com
Keywords: C3G; platelet secretome; angiogenesis; Vamp-7; metastasis
Received: July 05, 2017 Accepted: October 25, 2017 Published: November 06, 2017
Previous observations indicated that C3G (RAPGEF1) promotes α-granule release, evidenced by the increase in P-selectin exposure on the platelet surface following its activation. The goal of the present study is to further characterize the potential function of C3G as a modulator of the platelet releasate and its implication in the regulation of angiogenesis.
Proteomic analysis revealed a decreased secretion of anti-angiogenic factors from activated transgenic C3G and C3GΔCat platelets. Accordingly, the secretome from both transgenic platelets had an overall pro-angiogenic effect as evidenced by an in vitro capillary-tube formation assay with HUVECs (human umbilical vein endothelial cells) and by two in vivo models of heterotopic tumor growth. In addition, transgenic C3G expression in platelets greatly increased mouse melanoma cells metastasis. Moreover, immunofluorescence microscopy showed that the pro-angiogenic factors VEGF and bFGF were partially retained into α-granules in thrombin- and ADP-activated mouse platelets from both, C3G and C3GΔCat transgenic mice. The observed interaction between C3G and Vesicle-associated membrane protein (Vamp)-7 could explain these results. Concomitantly, increased platelet spreading in both transgenic platelets upon thrombin activation supports this novel function of C3G in α-granule exocytosis.
Collectively, our data point out to the co-existence of Rap1GEF-dependent and independent mechanisms mediating C3G effects on platelet secretion, which regulates pathological angiogenesis in tumors and other contexts. The results herein support an important role for platelet C3G in angiogenesis and metastasis.
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