Bone Morphogenic Protein 4 Produced in Endothelial Cells by Oscillatory Shear Stress Stimulates an Inflammatory Response

Abstract

Atherosclerosis is now viewed as an inflammatory disease occurring preferentially in arterial regions exposed to disturbed flow conditions, including oscillatory shear stress (OS), in branched arteries. In contrast, the arterial regions exposed to laminar shear (LS) are relatively lesion-free. The mechanisms underlying the opposite effects of OS and LS on the inflammatory and atherogenic processes are not clearly understood. Here, through DNA microarrays, protein expression, and functional studies, we identify bone morphogenic protein 4 (BMP4) as a mechanosensitive and pro-inflammatory gene product. Exposing endothelial cells to OS increased BMP4 protein expression, whereas LS decreased it. In addition, we found BMP4 expression only in the selective patches of endothelial cells overlying foam cell lesions in human coronary arteries. The same endothelial patches also expressed higher levels of intercellular cell adhesion molecule-1 (ICAM-1) protein compared with those of non-diseased areas. Functionally, we show that OS and BMP4 induced ICAM-1 expression and monocyte adhesion by a NF B-dependent mechanism. We suggest that BMP4 is a mechanosensitive, inflammatory factor playing a critical role in early steps of atherogenesis in the lesion-prone areas.Endothelial cells are constantly exposed to shear stress (a dragging force generated by blood flow), which controls cellular structure and function such as regulation of vascular tone and diameter, vessel wall remodeling, hemostasis, and inflammatory responses (1). The importance of various types of shear stress is highlighted by the focal development of atherosclerosis (2). Atherosclerosis preferentially occurs in the arterial regions exposed to unstable shear stress conditions in branched or curved arteries, whereas straight arteries exposed to unidirectional laminar shear (LS) 1 are relatively lesion-free (1-3). Atherosclerosis is now known as an inflammatory disease caused by endothelial dysfunction (3, 4). One of the first visible markers of endothelial dysfunction in the lesion-prone areas is upregulation of inflammatory adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and ICAM-1 (3-6). These endothelial adhesion molecules play essential roles in adhesion and recruitment of monocytes to the subendothelial layer (3, 4).How do unstable shear conditions such as low and oscillating shear stress (OS) cause inflammation in those lesion-prone areas, whereas LS exerts athero-protective effects? The opposite effects of LS and OS may be determined by differential expression of genes and proteins, ultimately inducing anti-and pro-inflammatory and atherogenic responses. Recently, several studies (7-10) have begun to address the initial question to determine the expression profiles of mechanosensitive genes. However, the functional importance of those genes has not been clearly established.Here, we report identification of a mechanosensitive gene, BMP4, by DNA microarray analyses and subsequent verification by a variety of additional approac...

Neurogenic Inflammation in Stress-Induced Termination of Murine Hair Growth Is Promoted by Nerve Growth Factor

“…Inflammatory processes have been linked to BMP4-up-regulation. 52,53 We thus hypothesize, that stress-induced inflammation may shift the BMP4/noggin balance toward BMP4, thereby increasing the p75NTR expression. Moreover, BMP4 is able to induce SP expression in naive neurons 54,55 thereby contributing to the increase of SP ϩ neurons observed in stressed catagen skin.…”

Laminar shear stress inhibits cathepsin L activity in endothelial cells

“…Confluent endothelial monolayers grown in 100-mm tissue culture dishes were exposed to an arterial level of unidirectional LS (15 dyn/cm 2 ) or OS with directional changes of flow at 1 Hz cycle (Ϯ5 dyn/cm 2 ) for 1 day by rotating a Teflon cone (0.5°cone angle) as described previously. 19 One hour before shear, the monolayers were washed and changed to 10 mL of fresh shear medium (the growth medium without serum).…”

“…Mouse aortic endothelial cells (MAEC) obtained from the thoracic aortas of C57/BL6 mice were isolated, cultured in growth medium (Dulbecco modified Eagle's medium [DMEM] containing 20% fetal bovine serum [FBS], 100 g/mL endothelial cell growth supplement [ECGS, Sigma], and 2.5 U/mL heparin) as described, 19 and used between passages 7 to 10. Confluent endothelial monolayers grown in 100-mm tissue culture dishes were exposed to an arterial level of unidirectional LS (15 dyn/cm 2 ) or OS with directional changes of flow at 1 Hz cycle (Ϯ5 dyn/cm 2 ) for 1 day by rotating a Teflon cone (0.5°cone angle) as described previously.…”

Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells

“…3,5,11 Importantly, recent studies confirmed a striking upregulation of BMP-2/4 in atherosclerotic lesions. [2][3][4] Despite the growing evidence for the physiological/pathophysiological importance of BMP-2 in blood vessels, the mechanisms regulating endothelial BMP-2 expression have not yet been elucidated. Previously, we 12 have demonstrated that in coronary arteries in hyperhomocysteinemia, vascular inflammation and upregulation of TNF-␣ are associated with an increased vascular BMP-2 expression.…”

“…Key Words: free radicals Ⅲ cytokines Ⅲ growth factors T he transforming growth factor superfamily member cytokine, bone morphogenetic protein-2 (BMP-2), was originally detected in cartilage and bone 1 ; however, recent studies from this and other laboratories demonstrated that vascular endothelial and smooth muscle cells are also a significant source of BMPs. [2][3][4][5][6] First genetic analysis of patients with primary pulmonary hypertension indicated that a vascular BMP-2/BMP receptor system plays an important role in vascular physiology. 7,8 Indeed, BMP-2 has been shown to regulate a host of cellular functions, 2,4,5,9 including cardiovascular development, 9 neovascularization in tumors, 10 and smooth muscle cell chemotaxis in response to vascular injury.…”