Tied Down by Shear Force

Abstract

Shear forces play an important role in the regulation of vascular function and structure. Since the initial demonstration of flow-dependent dilation, the critical role of the endothelium in sensing changes in intimal shear stress, and transducing these into changes in vascular tone, has been well recognized. [1][2][3] The moment-to-moment adjustments in arterial diameter involve the release of endothelial-derived vasoactive factors, in particular NO, and play a central role in optimizing the conductance of the large arterial tree and maintaining peak efficiency of the circulation even when subjected to profound changes in blood flow. 4 However, the mechanisms governing the longer-term adaptations of vascular diameter and branching are equally or even more important for ensuring the appropriate development, patterning, and structure of the arterial tree, but they have not been well characterized. Here, too, the endothelium plays a pivotal role in adapting the diameter of an artery to persistent changes in flow, 5 in this case by structural changes in the medial layers, rather than just vasomotion. 6 Although it is likely that endothelial-derived vasoactive factors such as NO 7 also play an important role in this process as well, the full cast of mediators of arterial remodeling remains to be defined.It is perhaps not surprising that many of the same factors that mediate angiogenesis during blood vessel development may contribute to the remodeling of blood vessels in response to changing flow conditions and vice versa. For example, endothelium-derived NO, the classical mediator of shearinduced changes in vascular diameter, has recently been recognized as an important downstream mediator of the angiogenic effects of a wide range of factors, including vascular endothelial growth factor (VEGF), 8 basic fibroblast growth factor (FGF), 9 and recently angiopoietin-1 (Ang-1). 10 The angiopoietins represent a family of angiogenic factors that bind to the endothelial-selective receptor tyrosine kinase (RTK), Tie2, 11 and mediate vascular maturation by inducing the recruitment of pericytes and smooth muscle to invest the nascent arterial media, causing enlargement and increasing the complexity of the developing vascular tree. There is evidence that vascular pressures influence the recruitment/ differentiation of mural cells in the microcirculation 12 and the Ang/Tie2 system represents an attractive candidate system for mediating chronic adaptation of blood vessels to longterm hemodynamic changes.In this issue of Circulation Research, Porat and colleagues 13 provide new insight into an unexpected contribution of a related RTK, Tie1, to changes in vascular structure in response to luminal hemodynamic conditions. Although sharing significant homology with Tie2, Tie1 has no known ligand, 14 and its function is very much a matter of debate. The present demonstration that Tie1 expression is exquisitely related to vascular regions exposed to disturbed flow in both physiological and pathological conditions is very suggestive of a r...

Remodeling of Blood Vessels

“…2,3 The results of the present model show for the first time that long-term regulation of both vessel diameter and wall thickness in terminal vascular beds can be explained quantitatively by assuming vascular reactions to hemodynamic and metabolic stimuli with uniform response characteristics. In this model, the equations and parameters representing structural changes in diameter and wall thickness resulting from a given set of stimuli are identical for every segment in the network.…”

“…[1][2][3][4][5] It is reasonable to assume that each vessel segment reacts, through regulation of gene expression and cellular functions, to the local conditions and stimuli that it experiences, according to a common set of genetically determined responses or "rules." 6 Continuous dynamic reactions according to such rules can in principle lead to development of structures that are functionally adequate and capable of adaptation to changing conditions.…”