Rap1B speeds up angiogenesis

Rap1B is a member of the Rap family of small GTPases, which function as molecular switches in signaling networks that control, among other processes, integrin-mediated cell adhesion, cadherin-mediated cell junction formation, and cell polarity, in part through the regulation of the actin cytoskeleton.¹  However, details of these signaling networks and the contribution of the individual members of the Rap family to various processes are only slowly emerging. Using homozygous Rap1B^−/− mutants, Chrzanowska-Wodnicka and colleagues now show that Rap1B plays an important role in angiogenesis.

The authors previously showed that the majority of Rap1B^−/− mutants die from embryonic bleeding,²  which prompted them to zoom in on endothelial cells and angiogenesis. In endothelial cells, Rap1B is the major isoform of Rap1. Using surviving Rap1B^−/− mice, they observed that angiogenesis into subcutaneously implanted VEFG- and bFGF-containing matrigels was strongly reduced. Also, angiogenesis in the retina was clearly delayed at 7 days after birth, which was concomitant with diminished endothelial-cell proliferation. Finally, microvessel sprouting from aortic rings under the influence of VEGF or bFGF was strongly affected in Rap1B^−/− mutant mice. Importantly, migration of isolated endothelial cells was reduced, indicating that this defect may be one of the causes of reduced angiogenesis.

The mechanism by which Rap1b mediates these effects remains, at this point, largely unresolved. Although an attenuation of bFGF- or VEGF-induced p38 MAPK activation (and a very moderate effect on p42 ERK) were found, the authors were careful not to rule out any indirect effects of loss of Rap1B on VEGF-induced proliferation and migration. Indeed, VEGF signaling is tightly coupled to integrin function, and the role of Rap1 in enhancing integrin-mediated cell adhesion is well established.¹  A second function of Rap1 is in the regulation of cell-cell junctions, which are crucial for proper functioning of the vasculature. For example, the cAMP-responsive Rap1-specific exchange factor Epac1 has recently been described as modulating endothelial junctions and barrier function.³  In addition, the relatively common vascular disease, cerebral cavernous malformation (CCM), is caused by mutations in a protein (CCM1) that interacts with Rap1 and affects endothelial barrier function.⁴  Perhaps it is therefore surprising to learn that loss of Rap1B does not appear to lead to a defect in endothelial junctions. It is possible that other related GTPases, like Rap1A, may compensate in this aspect.