TGFbeta signaling is initiated when the type I receptor phosphorylates the MAD-related protein, Smad2, on C-terminal serine residues. This leads to Smad2 association with Smad4, translocation to the nucleus, and regulation of transcriptional responses. Here we demonstrate that Smad7 is an inhibitor of TGFbeta signaling. Smad7 prevents TGFbeta-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFbeta type I receptor, thereby blocking the association, phosphorylation, and activation of Smad2. Furthermore, mutations in Smad7 that interfere with receptor binding disrupt its inhibitory activity. These studies thus define a novel function for MAD-related proteins as intracellular antagonists of the type I kinase domain of TGFbeta family receptors.

Early atherosclerotic lesions develop in a topographical pattern that strongly suggests involvement of hemodynamic forces in their pathogenesis. We hypothesized that certain endothelial genes, which exhibit differential responsiveness to distinct fluid mechanical stimuli, may participate in the atherogenic process by modulating, on a local level within the arterial wall, the effects of systemic risk factors. A differential display strategy using cultured human endothelial cells has identified two genes, manganese superoxide dismutase and cyclooxygenase-2, that exhibit selective and sustained up-regulation by steady laminar shear stress (LSS). Turbulent shear stress, a nonlaminar fluid mechanical stimulus, does not induce these genes. The endothelial form of nitric oxide synthase also demonstrates a similar LSSselective pattern of induction. Thus, three genes with potential atheroprotective (antioxidant, antithrombotic, and antiadhesive) activities manifest a differential response to distinct fluid mechanical stimuli, providing a possible mechanistic link between endothelial gene expression and early events in atherogenesis. The activities of these and other LSSresponsive genes may have important implications for the pathogenesis and prevention of atherosclerosis.Vascular endothelium, the single-cell-thick lining of the cardiovascular system, forms a multifunctional, dynamically mutable interface, that is responsive to a variety of pathophysiologic stimuli. Dysfunction of endothelial cells (EC), induced by systemic biochemical risk factors (e.g., hypercholesterolemia, hyperhomocysteinemia, and diabetes), is thought to play a critical role in the development of atherosclerotic vascular disease and its clinical complications (1-3). The strikingly nonrandom distribution of the earliest lesions of atherosclerosis in both humans and experimental animals has suggested to many that hemodynamic forces might be acting as local "biomechanical risk factors"; however, the exact nature of the biomechanical stimuli involved and their influences on EC pathobiology remain ill-defined (4-6). Arterial bifurcations and curvatures, where disturbed flow patterns (flow separation, flow reversal, low amplitude, and fluctuating wall shear stresses) occur, typically are "lesion-prone areas," whereas geometries associated with uniform laminar flow (oscillatory without flow reversal) and relatively constant (time-averaged) wall shear stresses, such as the straight tubular portions of the aorta and its primary tributaries, tend to be "lesion-protected areas" (7-9). Interestingly, these patterns are retained even in genetically modified animals in which systemic risk factors, such as markedly elevated levels of atherogenic plasma lipoproteins, are present (10). These observations indicate that EC may respond differentially to their local fluid mechanical environment, and thus contribute to the characteristic pattern of atherosclerotic lesion development.Although the molecular mechanisms responsible for atherosclerotic lesion initiati...

Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of cardiovascular diseases such as atherosclerosis. The localization of atherosclerotic lesions to arterial geometries associated with disturbed flow patterns suggests an important role for local hemodynamic forces in atherogenesis. There is increasing evidence that the vascular endothelium, which is directly exposed to various fluid mechanical forces generated by pulsatile blood flow, can discriminate among these stimuli and transduce them into genetic regulatory events. At the level of individual genes, this regulation is accomplished via the binding of certain transcription factors, such as NFκB and Egr‐1, to shear‐stress response elements (SSREs) that are present in the promoters of biomechanically inducible genes. At the level of multiple genes, distinct patterns of up‐ and downregulation appear to be elicited by exposure to steady laminar shear stresses versus comparable levels of non‐laminar (e.g., turbulent) shear stresses or cytokine stimulation (e.g., IL‐1β). Certain genes upregulated by steady laminar shear stress stimulation (such as eNOS, COX‐2, and Mn‐SOD) support vasoprotective (i.e., anti‐inflammatory, anti‐thrombotic, anti‐oxidant) functions in the endothelium. We hypothesize that the selective and sustained expression of these and related “atheroprotective genes” in the endothelial lining of lesion‐protected areas represents a mechanism whereby hemodynamic forces can influence lesion formation and progression.