P2ry12, a purinergic receptor, is involved in multiple biological functions. It plays a role in platelet function, hemostasis, and thrombosis as the platelet P2Y12 receptor for adenosine 5'diphosphate (ADP) [6]. It is also associated with inflammation, and its inhibition or genetic deficiency shows antitumor effects [6]. Additionally, it is expressed on microglia and is involved in microglial motility, migration, and regulation of neurovascular structure and function [2,3].

In atherosclerosis models (apoe -/- mice), inhibition of the P2RY12 receptor ameliorated lipid accumulation and VSMC-derived foam cell formation independent of LDL-c levels [1]. Activation of the receptor blocked cholesterol efflux via PI3K-AKT in VSMCs, while its genetic knockdown or pharmacological inhibition reversed this effect [1]. In microglia-related studies, P2RY12 -/- mice showed capillary dilation, blood flow increase, and impaired vasodilation, suggesting its role in regulating neurovascular structure and function through PANX1-P2RY12 coupling [3]. In a depression-like behavior model, inhibition of P2RY12 reduced inflammation and depression-like behaviors, and P2RY12 increased neuroinflammation to accelerate such behaviors via the NLPR3 inflammasome [4]. Also, genetic deletion of P2RY12 in mice induced sex-specific cellular perturbations with females more significantly affected [5]. In pancreatic cancer models, P2RY12-inhibitors reduced cancer-associated thrombosis and tumor growth [7].

In conclusion, P2ry12 is crucial in multiple biological processes and disease conditions. Gene knockout (KO) and conditional knockout (CKO) mouse models have been instrumental in revealing its role in atherosclerosis, neuroinflammation-related depression-like behaviors, regulation of neurovascular structure and function, and cancer-associated thrombosis and tumor growth. These models provide valuable insights into the underlying mechanisms, which may contribute to the development of therapeutic strategies for related diseases.

References:

1. Pi, Shulan, Mao, Ling, Chen, Jiefang, Yue, Zhenyu, Hu, Bo. 2020. The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis. In Autophagy, 17, 980-1000. doi:10.1080/15548627.2020.1741202. https://pubmed.ncbi.nlm.nih.gov/32160082/

2. Gómez Morillas, Albert, Besson, Valérie C, Lerouet, Dominique. 2021. Microglia and Neuroinflammation: What Place for P2RY12? In International journal of molecular sciences, 22, . doi:10.3390/ijms22041636. https://pubmed.ncbi.nlm.nih.gov/33561958/

3. Bisht, Kanchan, Okojie, Kenneth A, Sharma, Kaushik, Kuan, Chia-Yi, Eyo, Ukpong B. 2021. Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice. In Nature communications, 12, 5289. doi:10.1038/s41467-021-25590-8. https://pubmed.ncbi.nlm.nih.gov/34489419/

4. Liu, Jie, Yu, Enyan. . P2RY12 Increased Neuroinflammation to Accelerate Depression-like Behaviors by the NLPR3 Inflammasome. In Current neurovascular research, 19, 267-274. doi:10.2174/1567202619666220829110111. https://pubmed.ncbi.nlm.nih.gov/36043776/

5. Uweru, Ogochukwu J, Okojie, Akhabue K, Trivedi, Aparna, Cox, Kendall, Eyo, Ukpong B. 2024. A P2RY12 deficiency results in sex-specific cellular perturbations and sexually dimorphic behavioral anomalies. In Journal of neuroinflammation, 21, 95. doi:10.1186/s12974-024-03079-7. https://pubmed.ncbi.nlm.nih.gov/38622726/

6. Cattaneo, M. . P2Y12 receptors: structure and function. In Journal of thrombosis and haemostasis : JTH, 13 Suppl 1, S10-6. doi:10.1111/jth.12952. https://pubmed.ncbi.nlm.nih.gov/26149010/

7. Palacios-Acedo, Ana Luisa, Mezouar, Soraya, Mège, Diane, Dubois, Christophe, Panicot-Dubois, Laurence. 2021. P2RY12-Inhibitors Reduce Cancer-Associated Thrombosis and Tumor Growth in Pancreatic Cancers. In Frontiers in oncology, 11, 704945. doi:10.3389/fonc.2021.704945. https://pubmed.ncbi.nlm.nih.gov/34589424/