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High molecular weight kininogen regulates endothelial function

This study demonstrates that the bradykinin (BK) precursor, non‐enzymatic cofactor high molecular weight kininogen (HK), regulates endothelial function. HK circulates in complex with two different zymogens, namely, prekallikrein (PK) and factor XI (FXI). Both PK and FXI participate in the contact phase of blood coagulation through their binding to HK. The assembly and activation of the HK‐PK complex on endothelial cells results in the generation of BK and nitric oxide (NO). Since no clinical abnormality is apparent in patients with PK deficiency, investigations were performed to determine the functional role of HK on endothelial cells using a flow‐based assay. HK positively regulated endothelial cell function by modulating Ca2+‐dependent process and endothelial nitric oxide synthase (eNOS) function. The inhibitors of BK‐dependent signaling pathway impaired HK‐mediated signal transduction in endothelial cells. HKH20 and HOE140 significantly reduced HK‐ or HK/PK‐induced intracellular [Ca2+]i changes. This is a novel finding indicating that HK contributes to the maintenance of endothelial barrier function in the absence of PK. Taken together, these findings highlight a novel potential function for HK‐receptor‐mediated crosstalk in regulating endothelial cells and suggest that HK may serve as a cardioprotective peptide. This work was supported by NSF MRI 0619774, AHA and NCRR/NIH P20RR021929 to ZSM.