MyD 88 - dependent , superoxide - initiated

The Rockefeller University Press $30.00 J. Exp. Med. Vol. 205 No. 13 3159-3171 www.jem.org/cgi/doi/10.1084/jem.20081298 3159 The regulation of blood vessel size is closely coordinated to changes in blood fl ow. Initial variations in blood fl ow elicit reversible vasomotor responses, whereas sustained alterations in hemodynamic forces result in permanent structural changes aff ecting vessel external diameter and/or vessel wall thickness that are described as vascular remodeling ( 1, 2 ). These adaptive changes in vessel size and medial thickness serve to normalize abnormal vascular stresses initiated by developmental or physiological perturbations of hemodynamic forces. For example, increases in blood fl ow and shear stress after construction of an arteriovenous fi stula induce outward remodeling, whereas decreases in blood fl ow and shear stress caused by ligation of arterial branches result in inward remodeling ( 3, 4 ). Vascular remodeling is integral to the development of the vasculature and the progression of arterial disease. Attenuated fl ow in the embryo leads to defective vascular growth that compromises viability ( 5 ), and inward remodeling of arteries distal to fl ow-limiting occlusive lesions results in luminal loss that further exacerbates tissue ischemia ( 6, 7 ). The endothelium is responsible for the detection of shear stress and plays an essential role in fl ow-mediated vascular remodeling ( 8 ). Physical perturbation of various “ mechanoreceptors ” trigger a network of intracellular signaling pathways, collectively termed mechanotransduction, which activate several transcription factors, notably NF B, that regulate the expression of mechanosensitive genes and ultimately lead to vessel wall remodeling through cellular and extracellular matrix reorganization ( 9 ). The generation of reactive oxygen species CORRESPONDENCE George Tellides: [email protected]