Endoglin Regulates Cyclooxygenase-2 Expression and Activity

Abstract

Abstract-The endoglin heterozygous (Eng ϩ/Ϫ ) mouse, which serves as a model of hereditary hemorrhagic telangiectasia (HHT), was shown to express reduced levels of endothelial NO synthase (eNOS) with impaired activity. Because of intricate changes in vasomotor function in the Eng ϩ/Ϫ mice and the potential interactions between the NO-and prostaglandin-producing pathways, we assessed the expression and function of cyclooxygenase (COX) isoforms. A specific upregulation of COX-2 in the vascular endothelium and increased urinary excretion of prostaglandin E 2 were observed in the Eng ϩ/Ϫ mice. Specific COX-2 inhibition with parecoxib transiently increased arterial pressure in Engbut not in Eng ϩ/ϩ mice. Transfection of endoglin in L6E9 myoblasts, shown previously to stimulate eNOS expression, led to downregulation of COX-2 with no change in COX-1. In addition, COX-2 promoter activity and protein levels were inversely correlated with endoglin levels, in doxycyclin-inducible endothelial cells. Chronic NO synthesis inhibition with N -nitro-L-arginine methyl ester induced a marked increase in COX-2 only in the normal Eng ϩ/ϩ mice. N -nitro-L-arginine methyl ester also increased COX-2 expression and promoter activity in doxycyclin-inducible endoglin expressing endothelial cells, but not in control cells. The level of COX-2 expression following transforming growth factor-␤1 treatment was less in endoglin than in mock transfected L6E9 myoblasts and was higher in human endothelial cells silenced for endoglin expression. Our results indicate that endoglin is involved in the regulation of COX-2 activity. Furthermore, reduced endoglin levels and associated impaired NO production may be responsible, at least in part, for augmented COX-2 expression and activity in the

Endoglin Regulates the Activation and Quiescence of Endothelium by Participating in Canonical and Non-Canonical TGF-β Signaling Pathways

“…stimuli, including VEGF, and its attenuation is essential for formation of functional, mature blood vessel. A number of studies have shown that endoglin haploinsufficiency or downregulation results in decreased EC proliferation (Jerkic et al, 2006a;Li et al, 2000). Here we observed increased proliferation in Eng+/2 compared with Eng+/+ EC associated with increased rate of DNA synthesis as well as reduced rate of apoptosis.…”

The physiological role of endoglin in the cardiovascular system

“…In agreement with these data, Eng ϩ/Ϫ mice show a decreased NO synthesis and/or a decreased endothelial NO synthase (eNOS) expression (77,78,160). However, opposite results have been reported, in terms of vasodilation, using Eng ϩ/Ϫ mice.…”

Interaction between alk1 and blood flow in the development of arteriovenous malformations

“…Given the coincidence of expression of alk1 and edn1, and the loss of edn1 in alk1 mutants, it is logical to consider that loss of Edn1, a vasoconstrictive peptide, could lead to vasodilation and contribute to AVM development. A role for vasodilation in HHT1-associated AVM development has been previously suggested: in ENG-deficient endothelial cells, vasodilatory by-products of inefficient endothelial nitric oxide synthase activity are produced and prostaglandin synthesis is increased, resulting in enhanced vasodilation (Toporsian et al, 2005;Jerkic et al, 2006). Furthermore, downregulation of EDN1 has been reported in human brain AVM samples (Rhoten et al, 1997).…”