CEACAM1: a key regulator of vascular permeability

Abstract

SummaryCarcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) is an immunoglobulin-like cell surface co-receptor expressed on epithelial, hematopoietic and endothelial cells. CEACAM1 functions as an adhesion molecule, mainly binding to itself or other members of the CEA family. We and others have previously shown that CEACAM1 is crucial for in vivo vascular integrity during ischemic neo-vascularization. Here, we have deciphered the roles of CEACAM1 in normal and pathological vascularization. We have found that Ceacam1-/-mice exhibit a significant increase in basal vascular permeability related to increased basal Akt and endothelial nitric oxide synthase (eNOS) activation in primary murine lung endothelial cells (MLECs). Moreover, CEACAM1 deletion in MLECs inhibits VEGF-mediated nitric oxide (NO) production, consistent with defective VEGF-dependent in vivo permeability in Ceacam1-/-mice. In addition, Ceacam1-null mice exhibit increased permeability of tumor vasculature. Finally, we demonstrate that CEACAM1 is tyrosine-phosphorylated upon VEGF treatment in a SHP-1-and Src-dependent manner, and that the key residues of the long cytoplasmic domain of CEACAM1 are crucial for CEACAM1 phosphorylation and NO production. This data represents the first report, to our knowledge, of a functional link between CEACAM1 and the VEGFR2/Akt/eNOS-mediated vascular permeability pathway.

CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation

“…This suggests that CEACAM1-null tumor epithelial cells provide different angiogenic stimuli for the tumor microenvironment compared with CEACAM1-expressing tumor cells. Excessive endothelial tip cell formation indicates inappropriate endothelial responsiveness towards vascular endothelial growth factor in CEACAM1null hosts, which is in agreement with recent reports (Horst et al, 2006;Nouvion et al, 2010;Sawamiphak et al, 2010;Wang et al, 2010).…”

“…These observations are congruent with our previous reports that CEACAM1null mice exhibit defective neo-angiogenesis, and that CEACAM1 regulates vascular permeability and response to vascular endothelial growth factor via balancing endothelial nitric oxide synthetase activation (Horst et al, 2006;Nouvion et al, 2010). Inadequate activation of endothelial nitric oxide synthetase activity in endothelial cells may explain vessel dilation in CEACAM1null hosts, as the NO signaling pathway regulates vasodilation by the activation of cyclic guanosine monophosphate-regulated guanylyl cyclases and cyclic nucleotide phosphodiesterases (Francis et al, 2010).…”

“…Recently, CEACAM1 has been identified as an important regulator of basal as well as acute vascular permeability. Owing to hyperactivation of the endothelial nitric oxide synthetase, increased vascular permeability and reduced vessel maturation are observed in CEACAM1-deficient mice in normal and tumor vessels (Nouvion et al, 2010).…”

Carcinoembryonic Antigen–Related Cell Adhesion Molecule 1 Inhibits MMP-9–Mediated Blood–Brain–Barrier Breakdown in a Mouse Model for Ischemic Stroke

“…Recent reports highlighted the immunomodulatory role of CEACAM1 on myeloid and ECs at the inflammatory endothelial interface. 13,14,16,35,36 We and others described CEACAM1 as a regulator of vascular homeostasis and integrity decreasing basal and acute vascular permeability. [36][37][38] Under hypoxic conditions, CEACAM1 is up-regulated after hypoxic preconditioning in myocardial ischemia on myocardiocytes and endothelia and was suspected to elicit cardioprotective effects.…”

“…13,14,16,35,36 We and others described CEACAM1 as a regulator of vascular homeostasis and integrity decreasing basal and acute vascular permeability. [36][37][38] Under hypoxic conditions, CEACAM1 is up-regulated after hypoxic preconditioning in myocardial ischemia on myocardiocytes and endothelia and was suspected to elicit cardioprotective effects. 39 Furthermore, CEACAM1-expressing myeloid cells catalyze collateral formation and improve tissue perfusion after permanent femoral artery occlusion in mouse model for hindlimb ischemia.…”