IntroductionAtherosclerosis is a progressive disorder initiated by biomechanical forces in areas of the vascular tree subjected to disturbed blood flow and a number of systemic factors, including hyperlipidemia, smoking, and diabetes (1, 2). Lipid uptake by the vascular wall leads over time to a gradual buildup of atherosclerotic plaques. Once formed, the plaque continues to expand, leading to a gradual restriction in lumen diameter and compromise of blood flow. Under certain conditions, plaque rupture can precipitate intravascular thrombosis, resulting in complete and sudden interruption of the arterial blood supply. The buildup, growth, and rupture of the plaque have all been associated with the presence of systemic and vascular wall inflammation (3-5). Despite strong data linking vessel wall inflammation to atherosclerosis progression, the mechanism(s) of inflammation-induced atherosclerotic disease progression remains obscure (4), while efforts to halt disease progression by antiinflammatory therapies have failed in clinical trial (3).Recent studies have documented a high incidence of endothelial-to-mesenchymal transition (EndMT) in a number of pathological conditions associated with inflammation, such as myocardial infarction (6), cerebral cavernous malformations (7), portal hypertension (8), pulmonary hypertension (9), and vascular graft failure (10, 11) among others. EndMT is characterized by a change in phenotype of normal endothelial cells (ECs) that assume the shape and properties of mesenchymal cells (fibroblasts, smooth muscle cells [SMCs]), including enhanced proliferation and migration; secretion of extracellular matrix proteins, such as fibronectin and collagen; and expression of various leukocyte adhesion molecules.TGF-β has been identified as the central player in driving EndMT progression (12, 13), but the processes leading to activation of its signaling remain poorly defined. We have previously reported that a reduction in endothelial FGF-mediated signaling induced by knockout of either the key intracellular signal mediator FGF receptor substrate 2 α (FRS2α) (10) or the primary FGF receptor in the endothelium (FGF receptor 1 [FGFR1]) (14) activates TGF-β signaling, leading to EndMT.The unusual feature of FGFR1 biology is that FGFR1's expression in ECs is affected by certain inflammatory stimuli, including IFN-γ, TNF-α, and IL-1β, that induce a profound reduction in its expression (10). Since these are precisely the inflammatory mediators found in atherosclerotic plaques, we set out to investigate the occurrence and role of EndMT in atherosclerosis.Studies in cell culture and mouse models demonstrated that both oscillatory fluid shear stress and soluble inflammatory mediators reduced FGFR1 expression and signaling and promoted TGF-β signaling and EndMT. In addition, analysis of human coronary arteries demonstrated a strong correlation among endothelial FGFR1 expression, increased TGF-β signaling, and the appearance of EndMT with the severity of atherosclerosis. Together, these findings point to...

Atherosclerosis is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined. Here we show that endothelial TGFβ signaling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Inhibition of endothelial TGFβ signaling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These pro-inflammatory effects of endothelial TGFβ signaling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type specific therapeutic intervention aimed at control of this disease.

Highlights d TGF-bR2 ablation combined with hypercholesterolemia reprograms smooth muscle cells d Reprogrammed SMCs undergo clonal differentiation into varied mesenchymal lineages d Loss of normal aortic SMCs and increased non-SMC mass induce aortic aneurysms