Smooth Muscle Cell Changes During Flow-Related Remodeling of Rat Mesenteric Resistance Arteries

Abstract

Abstract-To obtain information on the molecular and cellular mechanisms of flow-induced arterial remodeling, we analyzed the morphology and smooth muscle cell (SMC) characteristics in rat mesenteric resistance arteries after interventions that decreased and increased flow. Juvenile male Wistar Kyoto rats were subjected to surgery that, compared with control arteries, provided arteries with chronic low flow and chronic high flow. Low flow resulted in a decreased passive lumen diameter, hypotrophy of the artery wall, and both loss and decreased size of SMCs. Time course studies, with intervention length ranging from 2 to 32 days of altered blood flow, showed that the narrowing of the lumen diameter in low-flow arteries appeared within 2 days and that an early dedifferentiation of SMC phenotype was indicated by markedly reduced levels of desmin mRNA. High flow resulted in an increased passive lumen diameter and in hypertrophy of the artery wall. The hypertrophy resulted from SMC proliferation because SMC number, measured by the 3D-dissector technique, was increased and immunohistochemical assessment of proliferating cell nuclear antigen also showed an increase. The widening of high-flow arteries required 16 days to become established, at which time desmin mRNA was reduced. This time was also required to establish changed wall mass in both low-flow and high-flow arteries. Apoptotic cells detected by TdT-mediated dUTP-biotin nick end labeling staining were mainly located in the medial layer, and evaluation of DNA fragmentation indicated that increased apoptosis occurred in both low flow and high flow. This study shows for the first time direct evidence that reduced and elevated blood flow in resistance arteries produce, respectively, decrease and increase in SMC number, with dedifferentiation of the SMCs in both cases.

Right coronary artery becomes stiffer with increase in elastin and collagen in right ventricular hypertrophy

“…Studies have demonstrated that a sudden increase in blood flow initiates an enlargement of the arterial lumen that progresses for months as the WSS tends to a homeostatic or normal level (23,25). A gradual increase in blood flow has been reported by several groups to result in outward hypertrophic remodeling of resistance (4,41,44,45,47) and conductive arteries (25,36,39). The flow-induced remodeling may be an attempt to maintain mechanical homeostasis (24,25).…”

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

“…The three-dimensionaldissector technique is more accurate to determine changes in cell number and size than the more rapid counting of nuclear profiles on hematoxylin-eosin-stained tissue sections. 9 Additional measurement of local transmural pressure and local blood flow at the various time points would have allowed to speculate on the extent to which normalization of wall stress and wall shear stress is impaired in mesenteric resistance arteries of DOCA-salt hypertensive rats. Figure 4 Schematic overview of changes in arterial lumen diameter and medial mass in relation to hypertension (blue arrow), imposed changes in flow (green arrow (high flow) and red arrow (low flow)), SOL1 treatment during hypertension (HT þ SOL-1: orange arrow) and age (purple arrow).…”

“…This is in line with the flow-induced outward hypertrophic remodeling reported previously. 9,27,30,31 It was, however, not accompanied by alterations in arterial wall stiffness (Figure 2g), the elastin to collagen ratio or the macrophage count (Table 1). Surprisingly, after 7 weeks exposure to elevated blood flow, the outward remodeling (Figure 1b) and the increases in lumen diameter (Ø: to 455±21 mm, NS, Figure 2b), in medial mass (mCSA: to 14±1 Â 10 3 mm 2 , NS, Figure 2d) and the hyperplasia (# nuclei: to 41±3, NS; Figure 2f), were no longer statistically significant compared with control (NF) arteries of the same normotensive rats.…”

“…Arteries from a distant part of the intestine were considered control arteries exposed to normal flow (NF). 9,27 After a 1-week recovery period, a DOCA pellet (100 mg, Sigma Aldrich, Zwijndrecht, The Netherlands) (n ¼ 28) or a control silicon pellet (n ¼ 29) was implanted subcutaneously. All animals were given high-salt drinking water (1% NaCl and 0.2% KCl).…”

“…8 The arterial changes in secondary and experimental hypertension, on the other hand, are mainly hypertrophic in nature and involve smooth muscle cell hypertrophy and/or hyperplasia. 8,9 Remodeling of the vascular wall in hypertension is also associated with changes in the composition of the extracellular matrix leading to increased stiffness. 10 Although anti-hypertensive therapy is mainly focused on lowering the blood pressure, preventing or reversing the arterial structural changes might be more beneficial for the morbidity and mortality of hypertensive patients.…”