Abstract
Imbalanced angiogenesis is a characteristic of several diseases. Rho GTPases regulate multiple cellular processes, such as cytoskeletal rearrangement, cell movement, microtubule dynamics, signal transduction and gene expression. Among the Rho GTPases, RhoA, Rac1 and Cdc42 are best characterized. The role of endothelial Rac1 and Cdc42 in embryonic development and retinal angiogenesis has been studied, however the role of endothelial RhoA is yet to be explored. Here, we aimed to identify the role of endothelial RhoA in endothelial cell functions, in embryonic and retinal development and explored compensatory mechanisms. In vitro, RhoA is involved in cell proliferation, migration and tube formation, triggered by the angiogenesis inducers Vascular Endothelial Growth Factor (VEGF) and Sphingosine-1 Phosphate (S1P). In vivo, through constitutive and inducible endothelial RhoA deficiency we tested the role of endothelial RhoA in embryonic development and retinal angiogenesis. Constitutive endothelial RhoA deficiency, although decreased survival, was not detrimental for embryonic development, while inducible endothelial RhoA deficiency presented only mild deficiencies in the retina. The redundant role of RhoA in vivo can be attributed to potential differences in the signaling cues regulating angiogenesis in physiological versus pathological conditions and to the alternative compensatory mechanisms that may be present in the in vivo setting.
Highlights
Imbalanced angiogenesis is a characteristic of several diseases
To investigate the role of endothelial RhoA in angiogenesis induced by stimuli activating diverse signaling pathways, we selected Vascular Endothelial Growth Factor (VEGF) and Sphingosine-1 Phosphate (S1P) as representative angiogenesis inducers through tyrosine kinase receptor[23,24] and G protein-coupled receptor signaling respectively[25]
Both VEGF and S1P stimulation induced RhoA activation in primary endothelial cells (HUVECs) and this induction was blocked by C3 toxin treatment (Fig. 1A,B)
Summary
Imbalanced angiogenesis is a characteristic of several diseases. Rho GTPases regulate multiple cellular processes, such as cytoskeletal rearrangement, cell movement, microtubule dynamics, signal transduction and gene expression. Small GTPases are actively involved in many steps of the angiogenic process, as the distinct role of RhoA, Rac[1] and Cdc[42] and others has been reported for endothelial cell migration, proliferation, basement membrane degradation, morphogenesis, capillary survival and barrier function[9]. They have all been demonstrated as downstream effectors of potent angiogenesis inducers, such as vascular endothelial growth factor (VEGF)[10] and sphingosine-1-phosphate (S1P)[11,12]. We engineered constitutive and inducible endothelial-specific RhoA deficiency through the Tie2-Cre and Cdh5-CreERT2 promoters respectively, studied the impact of endothelial RhoA deletion in embryonic survival and retinal angiogenesis, and compared the in vivo data with the in vitro outcome of RhoA deficiency in endothelial cell functions, under stimulation by potent angiogenesis inducers
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