Arterial smooth muscle cell phenotype in stroke-prone spontaneously hypertensive rats.

Abstract

The aim of this study was to determine the phenotype of smooth muscle cells in the arteries of chronically hypertensive animals and to analyze the effects of treatments known to increase the survival of the animal without a clear effect on its hypertensive state. Stroke-prone spontaneously hypertensive rats (SHRSP) kept on a 1% sodium drinking solution were untreated or treated with one of two diuretics, indapamide (3 mg/kg per day) or hydrochlorothiazide (20 nig/kg per day), from 6 to 13 weeks of age. Phenotype was characterized by the immunolabeling of arteries with antibodies raised against a cellular form (EIIIA) of fibronectin, <*-smooth muscle actin, and nonmuscle myosin. We demonstrated that phenotypes of smooth muscle cells of the SHRSP differ from those found in Wistar-Kyoto rats. The difference in phenotype is specific for the vessel type: ie, an increased expression of nonmuscle myosin in the aorta and of both EIIIA fibronectin and nonmuscle myosin in the coronary arteries. The two diuretics (1) had no effect on blood pressure, (2) prevented or did not prevent the increase in medial thickness, and (3) prevented changes in both smooth muscle cell phenotype and ischemic tissular lesions. Taken and/or hyperplasia of medial smooth muscle cells, develops in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 1 -2 Cardiac hypertrophy in hypertensive rats is correlated with a shift in the myosin heavy chain pattern of striated cardiac myocytes toward a fetal phenotype.3 Both quantitative and qualitative alterations may be normalized by antihypertensive treatment. 4 Changes in the phenotype of smooth muscle cells occur in vivo during ontogenesis.58 A well-differentiated phenotype is predominant in the vessels when cells contract in response to chemical and mechanical stimuli and are involved in the control of blood pressure and flow. At this stage, a-smooth muscle actin (aSM-actin) and smooth muscle myosin heavy chain (SM2) are the major contractile protein isoforms expressed in human, rat, or rabbit smooth muscle cells.6 -8 " A phenotypic shift in the expression of the contractile proteins 1 " 12 ' 3 and of a protein of the extracellular matrix, fibronectin, 14 toward the forms expressed in the fetus is observed in the aorta during the early phase of atherogenesis. Changes in the expression of fibronectin isoforms also occur in the coronary arteries and aorta as a result of pressure overload. In vivo, the heterogeneity of the smooth muscle cell phenotype throughout the vascular system in normotensive conditions 1718 would suggest specific changes in the phenotype of the smooth muscle cells as a result of hypertension. Therefore, the present study was conducted to determine whether an increase in size of the aortic and coronary artery mediae in SHRSP is associated with changes in the phenotype of the smooth muscle cells.It has been shown in the salt-loaded SHRSP that several types of drugs, such as angiotensin converting enzyme inhibitors, 1 /3-blockers, 19 and diuretics, 2 prevent the occurren...

Fibronectin Expression and Aortic Wall Elastic Modulus in Spontaneously Hypertensive Rats

“…14,[45][46][47] Moreover, several previous studies have demonstrated the presence of less-differentiated cells in the aortas of renovascular hypertensive rabbits and stroke-prone SHRs, as suggested by the increase in nonmuscle myosin heavychain content and medial hypertrophy. 41,48,49 Our finding of an increase in EIIIA FN and its receptor in SHRs is in keeping with these data, showing that some degree of a dedifferentiation process may occur in the aortas of SHRs. The mechanical properties assessed by the in vivo E inc -stress relationship depend on both the passive MEC behavior and the phenotypic characteristics of VSMCs.…”

“…These results were confirmed by Western blot analysis for total FN. To our knowledge, the only published immunohistochemical study of aortic EIIIA FN in hypertension is that by Contard et al, 41 which did not show any change in EIIIA FN in stroke-prone SHRs compared with Wistar-Kyoto rats. The apparent discrepancy between that study and ours may originate from different genetic models of hypertension (SHRs versus stroke-prone SHRs), the age of the animals used, and the method used for immunohistologic staining (freeze-dried, paraffin-embedded sections versus immunofluorescence).…”

Novel Mechanisms of the Antiproliferative Effects of Amlodipine in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats

“…We recently found that generation of Ang II in VSMC from SHR is associated with a change from the contractile to the synthetic phenotype, and that the change to the synthetic phenotype in SHR-derived VSMC also increases the expression of the growth factors of TGF-β1, PDGF A-chain, and bFGF through increased Ang II (33). VSMC proliferation and change to the synthetic phenotype contributes to the pathogenesis of atherosclerosis (34), neointimal formation after angioplasty (35) and hypertensive vascular diseases (36) in vivo.…”

Fibronectin

“…79 This proliferative phenotype is closely associated with a marked upregulation in ED-A-positive FN. 79,80 Furthermore, hypertension in different rat animal models has been shown to rapidly increase ED-A-positive FN expression (3-to 6-fold), correlating with the degree of blood pressure elevation; this expression is reversed by normalization of the blood pressure.…”

“…79 This proliferative phenotype is closely associated with a marked upregulation in ED-A-positive FN. 79,80 Furthermore, hypertension in different rat animal models has been shown to rapidly increase ED-A-positive FN expression (3-to 6-fold), correlating with the degree of blood pressure elevation; this expression is reversed by normalization of the blood pressure. [81][82][83] Similar to FN expression in atherosclerosis, angiotensin II rapidly increases FN expression in the aortic wall after a 3-day infusion, an effect that is inhibited by angiotensin II receptor blockade and occurs independently of the increase in blood pressure.…”