R-Ras Deficiency in Pericytes Causes Frequent Microphthalmia and Perturbs Retinal Vascular Development

Abstract

<b><i>Purpose:</i></b> The retinal vasculature is heavily invested by pericytes. Small GTPase R-Ras is highly expressed in endothelial cells and pericytes, suggesting importance of this Ras homolog for the regulation of the blood vessel wall. We investigated the specific contribution of pericyte-expressed R-Ras to the development of the retinal vasculature. <b><i>Methods:</i></b> The effect of R-Ras deficiency in pericytes was analyzed in pericyte-targeted conditional <i>Rras</i> knockout mice at birth and during the capillary plexus formation in the neonatal retina. <b><i>Results:</i></b> The offspring of these mice frequently exhibited unilateral microphthalmia. Analyses of the developing retinal vasculature in the eyes without microphthalmia revealed excessive endothelial cell proliferation, sprouting, and branching of the capillary plexus in these animals. These vessels were structurally defective with diminished pericyte coverage and basement membrane formation. Furthermore, these vessels showed reduced VE-cadherin staining and significantly elevated plasma leakage indicating the breakdown of the blood-retinal barrier. This defect was associated with considerable macrophage infiltration in the retina. <b><i>Conclusions:</i></b> The normal retinal vascular development is dependent on R-Ras expression in pericytes, and the absence of it leads to unattenuated angiogenesis and significantly weakens the blood-retinal barrier. Our findings underscore the importance of R-Ras for pericyte function during the normal eye development.

Akt3 activation by R-Ras in an endothelial cell enforces quiescence and barrier stability of neighboring endothelial cells via Jagged1

“…The disruption of Jagged1 impaired the barrier function between ECs and potentiated EC migration. Combining the current and previous findings, 21 – 23 , 27 , 28 , 30 accumulating evidence suggests that R-Ras shifts angiogenesis from the vessel sprouting process to the maturation process. R-Ras is strongly downregulated in proliferating ECs but highly expressed in non-proliferative ECs of mature blood vessels.…”

“… 22 , 29 On the other hand, pericyte-targeted Rras deletion causes blood-retina-barrier (BRB) breakdown and hypersprouting and branching of the developing capillary plexus in neonatal mouse retina. 30 The activation of Akt1 and Akt2 by R-Ras promotes lumen formation in sprouting blood vessels (endothelial tubulogenesis) by stabilizing microtubule cytoskeleton via inhibition of GSK-3β. 22 This pathway is required for producing new patent capillary vessels for the reperfusion of ischemic muscles and the subsequent muscle recovery.…”

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

“…Regardless of the missing points that would enhance our comprehension about how the function of Rho proteins and its up or downstream targets are modulated in endothelial cells during septic insults, these small G proteins have been consistently included in the physiological regulation of endothelial structure and function in different vascular systems [74][75][76][77][78][79][80][81][82][83][84][85][86][87]. In summary, the balanced activity of Rho proteins has been reported as mandatory to maintain several aspects of endothelial biology, including F-actin stabilization, contractility, and functional tight junctions (Figure 2A).…”

Selective Targeting and Tissue Penetration to the Retina by a Systemically Administered Vascular Homing Peptide in Oxygen Induced Retinopathy (OIR)

“…It is also needed for the proper lumenization of angiogenic blood vessels in hypoxia to obtain perfusion [61]. In the eye, loss of R-Ras in pericytes leads to defects in vascular supply and subsequent microphthalmia [62]. Concerning retinal diseases, R-Ras is crucial for blood vessel integrity and stabilization in the OIR-induced retinopathy [46].…”