Endothelial-Specific Deletion of Connexin40 Promotes Atherosclerosis by Increasing CD73-Dependent Leukocyte Adhesion

Abstract

Background-Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. In the present report, we sought to determine whether Cx40 contributes to the development of the disease. Methods and Results-Mice with ubiquitous deletion of Cx40 are hypertensive, a risk factor for atherosclerosis. Consequently, we generated atherosclerosis-susceptible mice with endothelial-specific deletion of Cx40 (Cx40del mice). Cx40del mice were indeed not hypertensive. The progression of atherosclerosis was increased in Cx40del mice after 5 and 10 weeks of a high-cholesterol diet, and spontaneous lesions were observed in the aortic sinuses of young mice without such a diet. These lesions showed monocyte infiltration into the intima, increased expression of vascular cell adhesion molecule-1, and decreased expression of the ecto-enzyme CD73 in the endothelium. The proinflammatory phenotype of Cx40del mice was confirmed in another model of induced leukocyte recruitment from the lung microcirculation. Endothelial CD73 is known to induce antiadhesion signaling via the production of adenosine. We found that reducing Cx40 expression in vitro with small interfering RNA or antisense decreased CD73 expression and activity and increased leukocyte adhesion to mouse endothelial cells. These effects were reversed by an adenosine receptor agonist. Key Words: atherosclerosis Ⅲ connexins Ⅲ endothelium Ⅲ gap junctions Ⅲ inflammation C ardiovascular diseases currently constitute the major cause of death in developed countries. 1 Atherosclerosis, an inflammatory disease of large and medium-sized arteries, 2 is the most important cause of cardiovascular diseases. The main consequences of atherosclerosis are myocardial infarction, cerebral infarction, and aortic aneurysm. 3 Conclusions-Cx40-mediated Clinical Perspective on p 131Atherosclerosis involves the formation of intimal lesions that are characterized by a dysfunctional endothelium, inflammation, lipid accumulation, cell death, and fibrosis. 2,3 The distribution of atherosclerotic plaques is highly characteristic in humans; the lesions develop predominantly near side branches of arteries where blood flow is disturbed. 4 A variety of substances mediating intercellular communication, including cytokines, chemokines, and growth factors, have been identified to induce, amplify, and modify the atherosclerotic inflammatory process. 5,6 In this context, connexins, a large family of proteins that form hemichannels and gap junction channels enabling transmembrane and intercellular coordination of tissue activity, 7,8 have been involved in atherogenesis. Three connexins are expressed in the vascular wall, namely connexin (Cx)37, Cx40, and Cx43, and important changes in their expression pattern have been reported in Received March 20, 2009; accepted October 28, 2009. From the Division of Cardiology (C.E.C., I.R., B.F., B.R.K.) and Department of Pediatrics (K.E.L.S., M.Z.R.S., M.B., B.F., T.D....

Regulation of CD73 in the development of lower limb atherosclerosis

“…In this respect, the individual differences in relation to adenosine receptor signaling in atherosclerotic disease progression remain a target for further studies. To this date, the contemporary literature quite clearly highlights the antiinflammatory role of CD73-mediated adenosine production [1,12] and its importance for vascular integrity and beneficial remodeling [2,21]. Thus, in accordance, we postulate that CD73 is elevated during the development of atherosclerosis to fight the disease and lost in the process of plaque maturity, plaque rupture, and adverse remodeling.…”

CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice

“…CD73 has been proposed to modulate lymphocyte-EC interactions as an adhesion molecule (30,31). Furthermore, CD73 plays important roles in vivo in maintaining the integrity of the vascular endothelium during hypoxia (32)(33)(34); in mediating efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis (35); and in regulating leukocyte adhesion to the endothelium during cardiac ischemia-reperfusion (36), atherosclerosis (37), cardiac allograft vasculopathy (38), and neointimal hyperplasia (39). In agreement, we recently demonstrated that CD73-generated adenosine regulates the ability of lymphocytes to migrate across high endothelial venules after LPS injection, thus limiting their access to inflamed LNs (20).…”

Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis

“…Connexin 40 mutant (Gja5 -/-), connexin 40 floxed (Gja5 flox/flox ), tamoxifen-inducible Tie2 Cre (Tie2CreERT2) and connexin 40-GFP reporter mice were as described (Chadjichristos et al, 2010;Forde et al, 2002;Miquerol et al, 2004;Simon et al, 1998 …”