Impact of bradykinin type 2 receptor overexpression on cardiovascular function in mice

Bradykinin is an endogenous peptide playing an important role in regulation of vascular function and permeability, but cardiovascular effects of endogenous bradykinin remain incompletely understood. We studied whether genetically engineered overexpression of endothelial bradykinin type 2 receptor (B₂) alters cardiac and vascular function using mice with endothelial-specific overexpression of B₂ (B₂^tg) and their transgene-negative littermates (B₂ⁿ). In the aorta, brain-stem and skeletal muscle of B₂^tg human BDKRB2 were exclusively expressed, and B₂-overexpression was evident by a significant upregulation of B₂ protein. Endothelium-dependent aortic relaxation and responses to phenylephrine or the nitric oxide (NO) donor measured ex vivo were unaffected by the transgene. In contrast, bradykinin induced constriction in B₂ⁿ, but i vasorelaxation in B₂^tg that was sensitive to inhibition of NO-synthase (NOS). In vivo assessment of endothelial function by flow-mediated dilation revealed no changes in B₂^tg as compared to B₂ⁿ. Likewise, transthoracic echocardiography showed no effect of B₂ overexpression on cardiac function. In contrast, decreased systolic blood pressure and bradycardia were observed in B₂^tg. The decrease in blood pressure in B₂^tg remained following inhibition of cyclooxygenase and NOS, but was completely abolished by the selective B₂ antagonist icatibant. Thus, endothelial-specific B₂-overexpression induced mild hypotension and bradycardia while having no effect on flow-mediated dilation or several cardiac function parameters. These minor effects of endothelial-specific B₂ overexpression in healthy mice suggest that alterations of endogenous bradykinin generation may not be associated with derangements of cardiovascular functions, however, the long-term safety of continuous changes of bradykinin in cardiovascular comorbidities deserves further rigorous clinical investigation.