C57BL/6JCya-S1pr2^em1flox/Cya

S1pr2, or sphingosine 1-phosphate receptor 2, is a key receptor that binds to sphingosine-1-phosphate, regulating various biological processes. It is involved in multiple signaling pathways such as RhoA/ROCK1, p38 MAPK/YAP, and Wnt3a/RhoA/ROCK1/β-catenin, which are crucial for functions like cell migration, activation, and barrier function regulation, and are of great biological importance in processes including angiogenesis, immune cell regulation, and tissue repair [1,2,3,7]. Genetic models, especially KO/CKO mouse models, are valuable tools for studying S1pr2.

In IBD, knockdown or pharmacological inhibition of S1pr2 in mice reversed intestinal vascular endothelial barrier damage and M1 macrophage polarization, suggesting its role in IBD pathogenesis through the S1PR2/RhoA/ROCK1 pathway [1]. In cholestatic liver fibrosis, S1pr2 deficiency in mice attenuated liver injury and collagen accumulation, indicating its role in promoting hepatic stellate cell activation via the S1PR2/p38 MAPK/YAP signaling pathway [2]. In cerebral infarction, activating S1pr2 in the thalamus augmented vascular autophagy, suppressing angiogenesis and aggravating neuronal damage, while knockdown of Rtn4 (which interacts with S1pr2) enhanced angiogenesis and improved cognitive function [3]. In biliary atresia, selective knockdown of macrophage S1pr2 in mice decreased ZBP1/p-MLKL-mediated necroptosis and collagen deposition [4]. In peripheral artery disease, EC-specific S1pr2 loss-of-function in mice enhanced post-ischemic angiogenesis and blood flow recovery, as S1pr2 inhibits the AKT/eNOS signaling pathway [5]. In cardiac ischemia-reperfusion injury, EC-specific S1pr2 loss-of-function lessened inflammatory responses and diminished injury, while gain-of-function aggravated injury, with S1pr2 initiating excessive mitochondrial fission via the RHO/ROCK1/DRP1 pathway [6]. In diabetic nephropathy, knockdown or pharmacological inhibition of S1pr2 in mice reversed endothelial mesenchymal transition and endothelial barrier dysfunction in glomerular endothelial cells [7].

In conclusion, model-based research, especially using KO/CKO mouse models, has revealed that S1pr2 plays essential roles in various biological processes. It is involved in the pathogenesis of multiple diseases including IBD, cholestatic liver fibrosis, cerebral infarction, biliary atresia, peripheral artery disease, cardiac ischemia-reperfusion injury, and diabetic nephropathy. Understanding S1pr2's functions provides insights into disease mechanisms and potential therapeutic targets for these conditions.