FGL2 prothrombinase contributes to the early stage of coronary microvascular obstruction through a fibrin-dependent pathway.

Background: Membrane-associated fibrinogen-like protein 2 (FGL2 prothrombinase, pFGL2) is abundantly expressed in activated microvascular endothelial cells (MVECs) and plays a crucial role in microthrombus formation in microcirculatory vasculature. It has been widely reported that coronary microvascular obstruction (CMVO) contributes to adverse outcomes following myocardial ischemia/reperfusion. However, the role of pFGL2 in CMVO is poorly understood.

Methods And Results: We aimed to identify the effect of MVECs-pFGL2 in CMVO using FGL2 knockout mice. As results, the MVECs-pFGL2 expression progresses significantly over 3 days and then gradually decreases, which is positively correlated with the extent of CMVO as detected by HE staining in wild type mice. Furthermore, FGL2 deficiency is correlated with decreased areas of no-reflow and necrosis as detected by Evans Blue and TTC staining and that it ameliorates cardiac dysfunction detected by hemodynamics in the early stage of CMVO. Moreover, fibrin deposition in microvasculature is significantly reduced in FGL2-deficient mice as evidenced by immunohistochemistry, MSB and Carstairs staining, along with the down-regulation of leukocyte adhesion and infiltration. Additionally, we observed that the FGL2 deficiency decreases macrophage infiltration and shifts the macrophage phenotype from pro-inflammatory (M1,) to anti-inflammatory (M2,) pattern in the early stage of CMVO.

Conclusion: These findings highlight the MVECs-pFGL2-fibrin pathway in the early stage of CMVO and provide insights into coagulation and inflammation for the coronary artery disease therapeutics.