Histamine H₂ receptor (HRH2) is closely associated with the development of cardiovascular and cerebrovascular diseases. However, systematic Hrh2 knockout mice did not exactly reflect the HRH2 function in specific cell or tissue types. To better understand the physiological and pathophysiological functions of endothelial HRH2, this study constructed a targeting vector that contained loxp sites flanking the ATG start codon located in Hrh2 exon 2 upstream and a neomycin (Neo) resistance gene flanked by self-deletion anchor sites within the mouse Hrh2 allele. The targeting vector was then electroporated into C57BL/6J embryonic stem (ES) cells, and positively targeted ES cell clones were micoinjected into C57BL/6J blastocysts, which were implanted into pseudopregnant females to obtain chimeric mice. The F1 generation of Hrh2^flox/+ mice was generated via crossing chimeric mice with wild-type mice to excise Neo. We also successfully generated endothelial cell-specific knockout (ECKO) mice by crossing Hrh2^flox/+ mice with Cdh5-Cre mice that specifically express Cre in endothelial cells and identified that Hrh2 deletion was only observed in endothelial cells. Hrh2^flox/+ and Hrh2^ECKO mice were normal, healthy and fertile and did not display any obvious abnormalities. These novel animal models will create new prospects for exploring roles of HRH2 during the development and treatment of related diseases.

组胺H ₂受体(HRH2)与心脑血管疾病的发生发展密切相关。然而，系统性的Hrh2敲除小鼠并不能准确反映特定细胞或组织类型中的 HRH2 功能。为了更好地了解内皮 HRH2 的生理和病理生理功能，本研究构建了一个靶向载体，该载体包含位于Hrh2外显子 2 上游的 ATG 起始密码子两侧的 loxp 位点和一个新霉素（Neo) 抗性基因，两侧是小鼠 Hrh2 等位基因内的自缺失锚定位点。然后将靶向载体电穿孔到 C57BL/6J 胚胎干 (ES) 细胞中，并将阳性靶向 ES 细胞克隆微注射到 C57BL/6J 囊胚中，将其植入假孕雌性以获得嵌合小鼠。Hrh2 ^{flox/ +}小鼠的 F1 代是通过将嵌合小鼠与野生型小鼠杂交以切除Neo 产生的。我们还通过将Hrh2 ^{flox/ +}小鼠与在内皮细胞中特异性表达 Cre 的 Cdh5-Cre 小鼠杂交，并确定仅在内皮细胞中观察到 Hrh2 缺失，从而成功地产生了内皮细胞特异性敲除 ( ECKO ) 小鼠。小时2^{FLOX / +}和Hrh2 ^ECKO小鼠均正常，身体健康，肥沃，没有表现出任何明显异常。这些新的动物模型将为探索 HRH2 在相关疾病的发展和治疗中的作用创造新的前景。