Bone Morphogenetic Protein-2 Induces Proinflammatory Endothelial Phenotype

Abstract

The transforming growth factor-␤ superfamily member bone morphogenetic protein-2 (BMP-2) is up-regulated in atherosclerotic arteries; however, its effects on the endothelium are not well characterized. Using microdissected coronary arterial endothelial cells (CAECs) and cultured primary CAECs, we demonstrated endothelial mRNA expression of BMP-2 and BMP-4. The proinflammatory cytokine tumor necrosis factor-␣ and H 2 O 2 significantly increased endothelial expression of BMP-2 but not BMP-4. In organ culture, BMP-2 substantially decreased relaxation of rat carotid arteries to acetylcholine and increased production of reactive oxygen species, events inhibited by pharmacologically blocking protein kinase C (PKC) or NAD(P)H oxidase. BMP-2 activated nuclear factor-〉 in CAECs, and BMP-2 and BMP-4 substantially increased adhesion of monocytic THP-1 cells, which was reduced by pharmacologically inhibiting p42/44 MAP kinase pathway (also by siRNA downregulating ERK-1/2) or PKC. Incubation of rat carotid arteries with BMP-2 ex vivo also increased adhesion of mononuclear cells to the endothelium, requiring p42/44 MAP kinase and PKC. Western blotting showed that in CAECs and carotid arteries BMP-2 elicited phosphorylation of p42/44 MAP kinase, which was reduced by blocking MAP kinase kinase and PKC. Collectively, expression of BMP-2 is regulated by proinflammatory stimuli, and increased levels of BMP-2 induce endothelial dysfunction, oxidative stress, and endothelial activation. The cytokine bone morphogenetic protein-2 (BMP-2), a transforming growth factor superfamily member, was originally detected in cartilage and bone 1 ; however, recent studies demonstrated that vascular endothelial and smooth muscle cells are also a significant source of BMPs.2-7 Genetic analysis of patients with primary pulmonary hypertension indicated that a vascular BMP-2/ BMP receptor system plays an important role in vascular physiology.8,9 BMP-2 is known to regulate a host of cellular functions, 2,4,5,10 including cardiovascular development, 10 neovascularization in bone 7 and tumors, 11 and smooth muscle cell chemotaxis.2 Endothelium-derived BMP-2 is osteoinductive 5,7 and hypotheses have been put forward that BMPs may contribute to vascular calcification. 3,5,12 Despite evidence for the physiological/ pathophysiological importance of BMP-2 the regulation of BMP-2 expression and the effects exerted by BMP-2 on endothelial function and phenotype have yet to be clearly elucidated.Previously, we have demonstrated that in coronary arteries in hyperhomocysteinemia vascular inflammation and up-regulation of tumor necrosis factor (TNF)-␣ is associated with an increased vascular BMP-2 expression. 13 Importantly, recent studies confirmed a striking up-regulation of BMPs in atherosclerotic lesions.2-4 BMP-4 (which is related to BMP-2 by its amino acid sequence but is transcribed from an entirely different gene) 4,6 was shown to exert proinflammatory effects by enhancing monocyte adhesion to the endothelium. On the basis of the aforementioned findings we h...

BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells

“…In addition, endothelial cells are major targets of proinflammatory cytokines such as TNF-α and interleukin-1β (IL-1β) and these proinflammatory cytokines regulate BMP-2 expression in pathological conditions. For example, studies by Csiszar et al showed that TNF-α increased BMP-2 expression in endothelial cells [19,27]. Thus, under inflammatory conditions, BMP-2 released from endothelial cells may act on adjacent SMC, induce osteochondrogenic differentiation and result in calcification in the arterial tree.…”

“…Multiple signaling pathways may involve in BMP-2 effects. Csiszar et al showed that ERK and PKC play important roles in BMP-2-induced proinflammatory phenotype in endothelial cells [19]. In addition, JNK and PI3-kinase are also involved in BMP-2-upregulated Pit-1 expression [20,21].…”

Increasing Risk of Osteoporotic Fracture Is Associated With Vascular Dysfunction and Abnormal Vascular Structure in Both Men and Women

“…18,29 Expression of BMP-2 is regulated by nuclear factor κ-B (NF-κB) activation, and BMP-2 impairs endothelial function through production of NADPH oxidase-derived reactive oxygen species. 29 Osteoprotegerin is a key cytokine that inhibits receptor activator of NF-κB ligand (RANKL)-mediated osteoclastic bone resorption. 18 Osteoprotegerin is expressed in endothelial cells and plays a pivotal role in vascular calcification and osteoporosis.…”

Activation of Receptor for Advanced Glycation End Products Induces Osteogenic Differentiation of Vascular Smooth Muscle Cells

“…In addition to its role in orthotopic bone formation, BMP2 is known to regulate a range of function of vascular endothelial cells and vascular SMC, including differentiation, proliferation, and apoptosis 37) . In particular, BMP2 expression increases in response to inflammatory cytokines, but also BMP2 itself potently induces the proinflammatory phenotype of endothelial cells by activating NF-kB 38) . Our present study provides novel findings suggesting that BMP2 elicits an osteo-inductive signal in VSMC, at least partly by collaboration with the RAGE signaling pathway.…”