Cross-Linking Vasomotor Tone and Vascular Remodeling

Abstract

Tightly regulated remodeling of arterial tissues is essential for survival in all vertebrate species. Arterial remodeling tunes development of the vasculature to the changing metabolic demands of embryonic tissues, it accommodates the extraordinary and diverse adjustments of cardiovascular function that occur at birth in both mother and neonate, and it adapts vascular structure to a host of physiological changes in adults. Arterial tissue remodeling also greatly influences the progression of the most important vascular pathologies including atherosclerosis, hypertension, and restenosis.1 Mechanical forces, particularly blood flow-derived shear stress, are potent stimuli for arterial remodeling. Large increases in shear stress elicit immediate vasodilation that is largely NO-dependent,2 and then a subsequent growth and remodeling selectively deliver new tissue in the circumferential direction to further increase vessel diameter. Conversely, decreased blood flow rate stimulates reduction in arterial diameter during some phases of development, in the postpartum maternal circulation, and in occlusive vascular pathologies.1 Early vasoregulation can be particularly important when shear stress is reduced because increases in vasomotor tone can cause substantial vasoconstriction, even in conduit arteries, and true remodeling often serves only to entrench the reduction in vessel diameter.3 The entrenchment of reduced vessel diameter during inward remodeling has important implications for the reversal of vascular pathologies after therapeutic interventions including bypass graft implantation, angioplasty, stenting, and antihypertensive therapy. But what does “remodeling” mean in this context? What causes the resetting of resting arterial diameter, and how do smooth muscle cells ultimately achieve a capacity to narrow diameter below that which previously characterized maximal constriction?3 Two recent studies have shed light on novel mechanisms by which constrictor responses can be converted to structural remodeling. Martinez-Lemus et al4 found that maintenance of norepinephrine-induced constriction for only 4 hours was sufficient to at least partially entrench the diameter …