Flow-Induced Vascular Remodeling in the Rat Carotid Artery Diminishes With Age

Abstract

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.

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

“…This age‐dependent remodeling was also observed in rats in which ligation of the left internal and external carotid arteries increased right carotid blood flow by 46%. After 4 weeks, the right carotid outer diameter increased and shear stress returned to initial values in juvenile but not adult rats 76. The constrained arterial remodeling and augmented shear stress set point of aged animals is strikingly similar to the phenotype we observed in nonreversed flow collateral segments.…”

Genetic determinants of vascular remodelling

“…These findings demonstrate significant strain-dependent differences in shear stress regulation and vascular remodelling in response to altered flow. Like our previous study (42) in Fischer rats, there was no change in media area and no neointima formation. However, we have chosen mice for our genetic analysis because the magnitude of the phenotypic differences (measured by changes in vessel wall components) was much greater.…”

“…Key requirements for our model included the ability to study both high and low flow, reproducibility, technical ease in establishing the change in flow, availability of multiple inbred strains, ability to perform physiological measurements, a sequenced genome with multiple polymorphic markers and low cost. Initially, we focused on rats because their larger size permitted development of the procedure and validation of the remodelling mechanism (41,42).…”

“…In Fischer rats, we developed a quantitative, highly reproducible model of carotid flow alteration that involved ligation of the left internal and external carotid arteries, leaving flow only through the occipital artery (42). Left common carotid artery (LCA) blood flow immediately decreased by approximately 93%, whereas flow in the contralateral right carotid artery (RCA) increased by approximately 46%.…”

Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

“…27,30,41,42 In the present study, we observed flowinduced outward hypertrophic remodeling but no hypotrophy in resistance arteries exposed to low blood flow in normotensive Wistar rats studied between 10 and 14 weeks of age. This indicates dependence of flow-related arterial remodeling on rat age 43 and strain. 44 Unexpectedly, no significant differences in diameter and media mass were observed between control arteries and arteries Flow-induced remodeling in DOCA-salt hypertension P Lemkens et al exposed to elevated blood flow for 7 weeks in normotensive rats.…”