Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress.

Abstract

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...

Endothelial basement membrane laminin 511 is essential for shear stress response

“…It was not possible to use laminin 411 as the cells detached under even low flow conditions due to weak adhesion. Prostacyclin is released from endothelial cells under flow‐induced shear (Frangos et al , 1985) and its expression is controlled by COX2 (Topper et al , 1996); hence, elevated COX2 expression reflects an enhanced shear response. Figure 3B shows a higher fold change in COX2 mRNA and protein expression in shear versus non‐shear conditions in HUAECs plated on laminin 511 compared with laminin 111, consistent with a role for laminin 511 in shear‐induced arterial dilation in vivo .…”

The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer

“…It is unlikely that this induction is cancer cell speci®c inasmuch as the endothelial cells, acinar and ductal cells, and ®broblasts also exhibited expression of Smad7 by in situ hybridization. Indeed, Smad7 was originally cloned from endothelial cells and the enhanced expression in this cell type is believed to promote endothelial cell proliferation (Topper et al, 1996.…”

“…Smad2/Smad4 and Smad3/Smad4 complexes then translocate to the nucleus where they regulate gene transcription (Heldin et al, 1997;. Two novel members of the Smad family, Smad6 and Smad7, were cloned from vascular endothelial cells (Topper et al, 1996Hayashi et al, 1997;Imamura et al, 1997). They associate with the activated TbRI, thereby blocking access and phosphorylation of Smad2 (Hayashi et al, 1997;Imamura et al, 1997) and possibly Smad3.…”

Glycosylation regulates turnover of cyclooxygenase‐2

“…In particular, we have found that the presence of AA in human prostate cancer cells up-regulates COX-2 mRNA and protein expression [14,15] -specifically, the 72 kDa glycoform [16]. However, COX-2 is also involved with normal physiological processes such as neurotransmission and synaptic activity [17,18], maintaining normal renal functions [19], providing vascular protection [20], regulating cerebral blood flow [21], and facilitating pregnancy [22].…”