Faktör XII'nin retinal vasküler ödem üzerine etkisi

Abstract

Kallikrein-kinin system(KKS) is a known mediator of vasogenic edema in patients with retinal vascular diseases. Although its effects are well characterized on vascular permeability and retinal thickness, the initiator of the pathway has not been elucidated. Factor XII (FXII); the main activator of KKS, cleaves plasma prekallikrein (PPK) to its active form plasma kallikrein (PKal). It has been previously shown that FXII is present in the vitreous of patients with Diabetic Macular Edema (DME), but its role is not yet available. In this study, we aim to characterize the role of FXII in retinal edema, and investigate tissue plasminogen activator(tPA) – plasmin pathway as an activator of KKS. tPA caused concentration dependent of KKS activation, which was dependent on the presence of FXII and plasminogen in human plasma. tPA didn’t directly interact with PPK or FXII, rather interacts via plasmin mediated cleavage of FXII. FXII cleaved by plasmin resulted in enzymatically active FXII fragments. tPA-mediated KKS activation occured in normal mouse plasma, and was not present in PKal- or FXII-deficient mice. Moreover, tPA mediated KKS activation resulted in HK cleavage, which was not present again in FXII or PKal knock-out mice. Intravenous administration of therapeutic tPA in mice resulted in in-vivo activation of KKS and cleavage of PPK to PKal. Next, we turned our attention to the role of FXII’s role in retinal vascular diseases. We showed that there is increased FXII activity in patients with DME which correlate with increased KKS components. We showed that KKS got activated in-vivo in VEGF-induced and bradykinin-induced retinal edema models. We revealed that FXIIa injection cause significant retinal edema compared to PBS, and PKal-deficient mouse shows %70 less thickening compared to wild-type counterparts. Our results suggest that fibrinolytic system is a pathophysiologic activator of KKS, and FXII promotes retinal thickening in retinal vascular disease models.