Endothelial cell-selective adhesion molecule modulates atherosclerosis through plaque angiogenesis and monocyte-endothelial interaction.

Endothelial cell-selective adhesion molecule (ESAM) is a new member of the immunoglobulin superfamily, which is expressed in vascular endothelial cells. Previous studies have demonstrated that ESAM regulates angiogenesis, endothelial permeability, and leukocyte transmigration. However, little is known concerning the role of ESAM in atherosclerosis. In this study, we assessed the effects of ESAM inactivation on atherosclerosis in mice. ESAM-/- mice were bred with apoE-/- mice to generate double knockout mice, and the aortic lesion size of apoE-/- and ESAM-/-apoE-/- mice was compared histologically. Although plasma cholesterol levels were higher in ESAM-/-apoE-/- mice, the lesion size was markedly smaller than in apoE-/- mice. ESAM-/-apoE-/- mice exhibited a decrease in the number of vasa vasorum and macrophages in the vessel wall. In vitro adhesion assays showed that THP-1 cells, which did not express ESAM, bound to the ESAM-coated culture plates, suggesting that ESAM may interact with heterophilic ligand(s) on monocytes. Moreover, downregulation of ESAM by siRNA in the endothelial monolayer diminished transendothelial migration of THP-1 cells. In conclusion, ESAM inactivation can reduce susceptibility to atherosclerosis by inhibiting plaque neovascularization and macrophage infiltration into the atheroma.

Role of endothelial cell-selective adhesion molecule in hematogeneous metastasis.

The spread of malignant cells from a localized tumor is thought to be directly related to the number of microvessels in the tumor. The endothelial cell-selective adhesion molecule (ESAM) is a member of the immunoglobulin superfamily that mediates homophilic interactions between endothelial cells. Previous studies have indicated that ESAM regulates angiogenesis in the primary tumor growth and endothelial permeability. In this study, we aimed to further elucidate the role of ESAM in tumor metastasis through angiogenic processes. ESAM expression was higher in hypervascular metastatic tumor tissues than in normal tissues in human lungs. Cell culture studies found that conditioned medium from B16F10 melanoma cells increased ESAM expression in endothelial cells and promoted endothelial migration and tube formation. The B16F10 medium-induced endothelial migration and tube formation were significantly attenuated when ESAM was downregulated by siRNA transfection. Intravenous injection of B16F10 cells into ESAM+/+ and ESAM-/- mice for comparison of metastatic potential resulted in the number of metastatic lung nodules in ESAM-/- mice being 83% lower than of those in ESAM+/+ mice. The microvascular density in the tumor was also lower in ESAM-/- than in ESAM+/+ mice. These findings indicate that ESAM regulates tumor metastasis through endothelial cell migration and tube formation in metastatic nodules. Inhibition of ESAM may therefore inhibit tumor metastasis by inhibiting the angiogenic processes.

Endothelial cell-selective adhesion molecule regulates albuminuria in diabetic nephropathy.

Microalbuminuria is a primary manifestation of diabetic nephropathy. Endothelial cell-selective adhesion molecule (ESAM) is a new member of the immunoglobulin superfamily which is selectively expressed by vascular endothelial cells. Although ESAM mediates homophilic interaction between endothelial cells, the role of ESAM in glomerular permeability remains unknown. We examined the expression and function of ESAM in the high glucose-induced microangiopathy in the kidney. ESAM was highly expressed in the glomerular endothelial cells, and the level was significantly reduced in the streptozotocin-induced diabetic mice. Stimulation of cultured endothelial cells with high glucose (35 mmol/l) resulted in a significant decrease in the ESAM expression compared to normal glucose (5.5 mmol/l). In vitro permeability assays revealed that albumin diffusion across endothelial monolayers was significantly increased when ESAM was knocked down by siRNA, suggesting that ESAM regulates vascular permeability of the glomeruli. To confirm these results in vivo, albuminuria was assessed using ESAM-/- mice. Urinary albumin to creatinine ratio in ESAM-/- mice was significantly higher than in ESAM+/+ mice. Transmission electron microscopy revealed that glomerular endothelial fenestration was decreased and endothelial tight junction was irregular and relatively wider in ESAM-/- mice than in ESAM+/+ mice. In conclusion, hyperglycemia downregulates ESAM and increases glomerular endothelial permeability. Thus, ESAM may regulate albumin extravasation at the glomeruli and play a role in the initiation of diabetic nephropathy.