Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1–deficient mice

Abstract

Platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31), a 130-kDa glycoprotein member of the Ig superfamily of transmembrane proteins, is expressed on endothelial cells, platelets, and subsets of leukocytes. It functions as a cell adhesion molecule as well as a scaffolding molecule capable of modulating cellular signaling pathways. In this study, using PECAM-1-deficient (KO) mice, as well as cells derived from these mice, we demonstrate that the absence of PECAM-1 expression is associated with an early onset of clinical symptoms during experimental autoimmune encephalomyelitis (EAE), a mouse model for the human autoimmune disease multiple sclerosis. During EAE, mononuclear cell extravasation and infiltration of the CNS occur at earlier time points in PECAM-KO mice than in wild-type mice. In vitro, T lymphocyte transendothelial migration across PECAM-KO endothelial cells is enhanced, regardless of expression of PECAM-1 on transmigrating T cells. Additionally, cultured PECAM-KO endothelial cells exhibit prolonged permeability changes in response to histamine treatment compared with PECAM-1-reconstituted endothelial cells. Lastly, we demonstrate an exaggerated and prolonged CNS vascular permeability during the development of EAE and a delay in restoration of dermal vascular integrity following histamine challenge in PECAM-KO mice.

Impaired tumor angiogenesis and VEGF-induced pathway in endothelial CD146 knockout mice

“…Secondly, embryogenesis is a more complex process in mice than that in zebrafish. A variety of endothelial cell adhesion molecules share certain functions with CD146 in angiogenic processes, such as JAM (Dejana et al, 2001), PECAM-1 (Graesser et al, 2002; Gratzinger et al, 2003) and ESAM (Hirata et al, 2001). All of these adhesion molecules might play overlapping roles with CD146, and could thus be able to compensate for its deletion in vivo during mouse embryogenesis, resulting in normal physiological angiogenesis in CD146 EC-KO mice.…”

Endothelial functions of platelet/endothelial cell adhesion molecule-1 (CD31)

“…Ferrero demonstrated twenty years ago that addition of anti-PECAM-1 antibodies to endothelial cell monolayers in culture increases the rate of albumin transit in transwells, that transfection of PECAM-1 into cultured fibroblasts reduces albumin transit, and that injection of the PECAM-1 mAbs into mice results in fluid leak into the hepatic and renal vasculature [74]. Though PECAM-1-deficient mice exhibit no vascular abnormalities while sitting quietly in a cage in an animal facility, they have a profound, easily observable phenotype when subjected to inflammatory [75–77] or hemostatic [78] challenge.…”

Control of vascular permeability by adhesion molecules

“…102 PECAM knockouts also exhibit increased survival when challenged with endotoxin, 103 and an earlier incidence of experimental autoimmune encephalitis. 104 In addition, endothelial cells isolated from PECAM deficient animals demonstrate increased leak in response to LPS 103 and histamine. 104 While the intracellular pathways regulated by PECAM-1 are not completely defined, PECAM-1 mediated interactions can lead to activation of PLC-g, 105 Akt and upregulation of eNOS via STAT3, 106 or increased Gaq/11 signaling.…”

“…104 In addition, endothelial cells isolated from PECAM deficient animals demonstrate increased leak in response to LPS 103 and histamine. 104 While the intracellular pathways regulated by PECAM-1 are not completely defined, PECAM-1 mediated interactions can lead to activation of PLC-g, 105 Akt and upregulation of eNOS via STAT3, 106 or increased Gaq/11 signaling. 107 One interesting signaling mechanism involves the Immunoreceptor Tyrosine-based Inhibitory Motif, or ITIM domain, in the PECAM-1 cytoplasmic tail.…”