Increased formation of functional caveolae due to increased content of fibrinogen

Abstract

Previously, we showed that elevated level of fibrinogen (Fg) increase endothelial cell (EC) layer permeability through formation of filamentous actin and affecting EC junction proteins. These changes led to an increase in mouse pial venular permeability. We hypothesized that Fg‐mediated increased EC layer permeability may also involve transcellular transport pathway. Formation of caveolae was observed in mouse brain cortical cryo‐sections obtained from wild‐type or matrix metalloproteinase‐9 gene knockout (MMP9−/−) mice after infusion of Fg (a total blood content of 4 mg/ml) or similar volume of PBS. Expression of caveolin‐1 and plasmalemma vesicle associated protein‐1 (PV‐1) were increased in mouse brain vessels after Fg infusion compared to those after PBS infusion. These effects were ameliorated in MMP9−/− mice. Expression of PV‐1 was increased by 15±4% and expression of occludin decreased by 3±1% in mouse pial vessels after infusion of Fg. At higher levels Fg increased formation of functional caveolae in mouse brain ECs (MBECs) as detected by caveolar uptake of albumin. Fg‐induced enhanced formation of caveolae in MBECs was mitigated by inhibition of MMP9 activity. These results suggest that high levels of Fg increase cerebrovascular permeability by altering both paracellular and transcellular pathways. It is still need to be defined which one of these pathways is most affected by elevated levels of Fg.