Divergent Functions of Rap1A and Rap1B in Endothelial Biology and Disease

Abstract

Rap1A and Rap1B are closely related small GTPases that regulate endothelial adhesion, vascular integrity, and signaling pathways via effector domain interactions, with downstream effectors controlling integrins and cadherins. Although both isoforms are essential for vascular development, recent studies using endothelial-specific knockout models have uncovered distinct, non-redundant functions. Rap1B is a key regulator of VEGFR2 signaling, promoting angiogenesis, nitric oxide production, and immune evasion in tumors while restraining proinflammatory signaling in atherosclerosis. In contrast, Rap1A unexpectedly functions as a modulator of endothelial calcium homeostasis by restricting Orai1-mediated store-operated calcium entry, thereby limiting inflammatory responses and vascular permeability. New insights into Rap1 regulation highlight the roles of context-specific guanine nucleotide exchange factors, such as RasGRP3, and non-degradative ubiquitination in effector selection. Emerging data suggest that isoform-specific interactions between the Rap1 hypervariable regions and plasma membrane lipids govern their localization to distinct nanodomains, potentially influencing downstream signaling specificity. Together, these findings redefine the roles of Rap1A and Rap1B in endothelial biology and highlight their relevance in diseases such as tumor angiogenesis, atherosclerosis, and inflammatory lung injury. We discuss the therapeutic implications of targeting Rap1 isoforms in vascular pathologies and cancer, emphasizing the need for isoform-specific strategies that preserve endothelial homeostasis.

Keywords: Rap GEF (Rap1 Guanine nucleotide Exchange Factor); Rap1A; Rap1B; RasGRP3; VEGFR2; angiogenesis; calcium signaling; inflammation; nitric oxide; vascular immunosuppression; vascular permeability.

Figure 1

Endothelial Rap1B is essential for VEGF-induced vascular immunosuppression. Endothelial Rap1B suppresses NF-κB–driven expression of cell adhesion molecules (VCAM1, ICAM1), limiting T-cell adhesion and recruitment. In the tumor microenvironment, VEGF–VEGFR2 signaling enhances this immunosuppressive effect through Rap1B, promoting endothelial quiescence and barrier to immune infiltration.

Figure 2

Rap1A restricts Orai1-mediated calcium entry to suppress inflammatory signaling in endothelial cells. The schematic illustrating the RasGRP3–Rap1A signaling axis in endothelial cells. Upon GPCR activation, phospholipase C (PLC) hydrolyzes PIP2 into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates RasGRP3, a diacylglycerol-sensitive guanine nucleotide exchange factor that activates Rap1A. Activated Rap1A suppresses store-operated calcium entry (SOCE) by limiting Orai1 activation and expression. In the absence of Rap1A, increased calcium influx via Orai1 promotes nuclear translocation of NFAT and transcription of proinflammatory genes such as CXCL1 and IL6, leading to pulmonary edema and inflammation. This pathway identifies Rap1A as a critical negative regulator of calcium-driven endothelial inflammation.