Vascular remodeling is regulated by a combination of hemodynamic, environmental, and genetic factors and may be influenced by age. To evaluate age-dependent remodeling in rats, we developed and used a quantitative highly reproducible model of carotid flow alteration. Fourteen juvenile (99+/-3 g) and 9 adult (199+/-5 g) male inbred Fischer rats underwent ligation of the left internal and external carotid arteries under anesthesia. Left common carotid blood flow immediately decreased by approximately 93%, whereas flow in the contralateral carotid increased by approximately 46%. After 4 weeks, the left carotid outer diameter (OD) significantly decreased in both juvenile and adult rats (as measured in vivo and by histological morphometry) compared with sham-operated rats. Changes in shear stress acutely mirrored the changes in blood flow. OD increased and shear stress returned to initial values after chronic exposure to increased flow in juvenile but not adult rats. To develop a simple quantitative index of remodeling that would not require killing the animals, we measured the OD in vivo and compared the ratio of right to left OD (OD ratio [ODR]) between groups. The initial ODR for all groups was approximately 1.0. After 4 weeks of altered flow, the ODR was significantly greater in juvenile than in adult rats (1.48+/-0.05 versus 1.29+/-0.04, respectively; P=.030), indicating that juvenile rats experienced more extensive remodeling than did the adult rats. We also found that unilateral carotid ligation caused a left versus right difference in endothelial NO synthase protein levels after 4 weeks that was not present in the sham-operated animals. Thus, the model described here shows that flow-induced vascular remodeling is dependent on age and supports the hypothesis that the driving force for remodeling involves shear stress and possibly NO. Because the model is quantitative, it allows dissection of the genetic factors that regulate remodeling in inbred rat strains.
Blood flow and the tractive force shear stress are important determinants of artery caliber, and reduced shear predisposes arteries to intimal thickening and atherosclerosis. The molecular basis for shear-induced changes in artery wall structure is poorly defined. A number of factors associated with normal and pathological artery wall remodeling are induced by shear stress in endothelial cell cultures. These include platelet-derived growth factor (PDGF), a potent mitogen, chemoattractant, and vasoconstrictor. To determine whether similar changes occur in vivo, we examined the effects of reduced blood flow on endothelial cell PDGF expression and proliferation in the rat carotid artery. Branches of the right internal and external carotid arteries were ligated, reducing common carotid artery blood flow from 8.0+/-0.6 to 0.5+/-0.1 mL/min while increasing flow in the left carotid from 7.1+/-0.6 to 10.8+/-0.7 mL/min. Shear stress following the procedure was 1.4+/-0.2 and 33.4+/-1.1 dyne/cm2 in carotids with reduced blood flow (RF) and increased blood flow (IF), respectively. Arteries were harvested 6, 24, 48, or 72 hours after ligation, perfusion-fixed, and opened longitudinally. Endothelial cell proliferation (bromodeoxyuridine [BrdU] labeling) was assessed en face at 24, 48, and 72 hours; expression of mRNA for PDGF-A and -B chains and PDGF alpha- and beta-receptors (in situ hybridization) was determined at 6, 48, and 72 hours after unilateral flow reduction. RF induced endothelial cell proliferation, which peaked at 48 hours (RF BrdU labeling: 24 hours, 0.4+/-0.2%; 48 hours, 7.2+/-2.0%; and 72 hours, 4.1+/-0.6%; n=5). PDGF-B expression increased in RF compared with IF endothelium within 48 hours and persisted at 72 hours (percent labeling [RF/IFx100]: 6 hours, 76+/-20%; 48 hours, 395+/-179%; and 72 hours, 208+/-44%; n=3). PDGF-A expression was similarly increased in RF endothelium. In contrast, expression of PDGF alpha- and beta-receptors was undetectable in RF and IF endothelium at all times. We conclude that endothelial cell PDGF ligand expression is induced by reduced shear stress in vivo and may play an important role in flow-mediated remodeling and atherogenesis.
Vasodilation following the infusion of acetylcholine is due to the release of endothelium-derived relaxing factor (EDRF). However, the role of EDRF in neurogenic coronary vasodilation, when acetylcholine is released outside the vessel at the adventitial-medial junction, has not been established. The action of EDRF in parasympathetic coronary vasodilation was tested in the present study using a specific inhibitor of EDRF synthesis, nitro-L-arginine methyl ester (L-NAME). Experiments were conducted on closed-chest, alpha-chloralose-anesthetized dogs with the heart paced at a constant rate. Phentolamine and propranolol were administered to block alpha- and beta-adrenergic receptors, and ibuprofen was given to inhibit prostaglandin synthesis. Intracoronary infusion of L-NAME decreased the coronary vasodilation in response to intracoronary acetylcholine or vagal stimulation. The coronary response to the endothelium-independent vasodilator nitroglycerin was unaffected by L-NAME. These data demonstrate that L-NAME specifically inhibits coronary vasodilation caused by acetylcholine and vagal stimulation, indicating that parasympathetic coronary vasodilation is dependent on EDRF.
It is usually assumed that the increase in coronary blood flow observed with norepinephrine occurs through local metabolic vasodilation secondary to cardiac beta-receptor activation. However, direct feedforward beta-receptor-mediated coronary vasodilation is also a possibility. In dogs with alpha-receptor blockade, the left circumflex artery was perfused at constant pressure. The vasodilator effect of intracoronary norepinephrine injections was determined during prolonged diastoles to avoid the chronotropic and intropic effects of norepinephrine. Norepinephrine caused a dose-dependent increase in coronary blood flow that was attenuated by both the selective beta 1-antagonist practolol and the selective beta 2-antagonist ICI 118,551. These data indicate that norepinephrine activates beta 1- and beta 2-receptors in coronary resistance vessels to cause vasodilation independent of inotropic and chronotropic effects. The physiological significance of coronary beta-receptor-mediated vasodilation was investigated in the beating heart. The coronary blood flow response and coronary venous oxygen tension response were compared when myocardial oxygen consumption was increased over the same range by one of three positive inotropic interventions: (1) norepinephrine, (2) paired-pulse stimulation, or (3) norepinephrine after alpha-blockade. During norepinephrine infusion (intervention 1), coronary venous oxygen tension decreased, indicating that the match between myocardial oxygen consumption and oxygen delivery is not maintained when coronary blood flow is controlled by alpha- and beta-receptors in addition to local metabolic factors. Paired-pulse stimulation (intervention 2) also resulted in a decrease in coronary venous oxygen tension, demonstrating that the balance between oxygen consumption and delivery is not maintained when blood flow is controlled by local metabolic factors alone. However, when coronary beta-receptor-mediated vasodilation was unmasked by alpha-blockade, norepinephrine infusion (intervention 3) produced no change in coronary venous oxygen tension. Therefore, coronary beta-receptor vasodilation helps maintain the balance between flow and metabolism in a feedforward manner in the beating heart.
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