Abstract-Angiotensin II (Ang II) may induce arterial hypertrophy either directly or through an increase in arterial pressure. To separate these 2 mechanisms, rats were implanted with osmopumps delivering either Ang II (100 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or saline. 5-Bromo-2Ј-deoxyuridine (BrdU) was delivered to both groups by osmopump (2.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Half of the rats in each group were given minoxidil (9 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) in their drinking water. After 14 days, systolic blood pressure was 117Ϯ2, 124Ϯ3, and 115Ϯ2 mm Hg in the control, Ang II-minoxidil, and minoxidil groups, respectively, and 181Ϯ6 mm Hg in the Ang II group (PϽ0.05). After perfusion-fixation, the thoracic aorta, carotid artery, small mesenteric artery, external spermatic artery, and kidneys were harvested, paraffin-embedded, and used for morphological measurements, immunohistochemistry for BrdU, and in situ hybridization with a 35 S-labeled riboprobe for platelet-derived growth factor-A chain (PDGF-A) mRNA. The walls of the aorta and carotid arteries hypertrophied in the Ang II group only. There were no significant morphological differences in the small arteries. BrdU was negative in all arteries but positive in the renal tubules. Expression of PDGF-A was elevated 8-fold in the thoracic aorta of the Ang II group (PϽ0.05). These results show that (1) arterial hypertrophy from Ang II infusion occurs in response to elevated arterial pressure, (2) hypertrophy was not associated with hyperplasia or polyploidy of vascular smooth muscle cells, and (3) PDGF-A expression correlated with elevated pressure and arterial wall hypertrophy. (Hypertension. 1998;32:452-458.) Key Words: pressure Ⅲ angiotensin II Ⅲ hypertrophy Ⅲ growth substances H ypertension is characterized by structural alterations of the vasculature, depending on the size and function of the particular vessel. During the course of hypertension, the larger arteries hypertrophy 1,2 while the lumen diameter of smaller arterioles is reduced without a change in crosssectional wall area.3,4 The lumen reduction in absence of hypertrophy is termed "inward eutrophic remodeling" and was first reported on the submucosal arterioles of the intestine in hypertensive individuals. 5 The small arteries (150 to 250 m ID) are found at the overlap where hypertrophy decreases and eutrophic remodeling begins, wherein they experience either an inward eutrophic or hypertrophic remodeling depending on the type of hypertension. 6,7 Many factors have been proposed to explain the structural alterations that occur during hypertension. One is the hormone angiotensin II (Ang II), which is a hypertrophic and hyperplastic stimulus of vascular smooth muscle cells, 8,9 as well as an inducer of platelet-derived growth factor-A chain (PDGF-A) expression.10 A second factor is elevated intravascular pressure itself. Like Ang II, elevated pressure is also considered a hypertrophic stimulus 2,11,12 and is linked to PDGF-A expression.13 As a consequence of the effect of Ang II on blood pressure, it is often difficult to distinguish...

This study was designed to determine whether pressure-induced expression of early response genes in the arterial wall is dependent on an increase in cell stretch or an increase in wall stress. Mesenteric arteries (245 to 385 microm in diameter) were isolated from Wistar rats and subjected to static pressures of either 90 mm Hg (control), 140 mm Hg, or 165 mm Hg for a period of 3 hours. Arteries developed a range of myogenic tone such that wall stresses in the 140 and 165 mm Hg arteries (1.60 to 4.44x10(6) dynes/cm2) were equivalent in some cases to those of controls (1.76 to 2.63x10(6) dynes/cm2). Vessels subjected to 140 or 165 mm Hg intraluminal pressure had diameters ranging from 74% to 104% of their relaxed diameter at 90 mm Hg, whereas control vessel diameters ranged from 88% to 100%. At the end of each experiment, vessels were fixed in 10% formalin, embedded in paraffin, and sectioned for in situ hybridization. Wall stress significantly correlated with c-myc mRNA and 18S rRNA expression. Gene expression did not correlate with vessel diameter, expressed as a percentage of the relaxed diameter at 90 mm Hg, ie, cell stretch. The expression of beta-actin mRNA did not differ between vessels and showed no correlation with wall stress, suggesting that the induction of c-myc mRNA and 18S rRNA was part of a specific response. These findings show that in an isolated artery, a pressure stimulus can be perceived as an increase in wall stress, independently of cell stretch. Therefore, wall stress may be the signaling parameter in hypertension where arteries are tonically constricted. The inhibition of gene expression by myogenic constriction may explain why hypertrophy takes place in large arteries during hypertension but not in arterioles where increased tone reduces wall stress.

Dobrian, Anca, Suzanne S. Wade, and Russell L. Prewitt. PDGF-A expression correlates with blood pressure and remodeling in 1K1C hypertensive rat arteries. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H2159-H2167, 1999.-We previously demonstrated remodeling of large and small arteries in angiotensin II-treated rats, paralleled by an increased expression of platelet-derived growth factor (PDGF)-A chain mRNA in large arteries. Both remodeling and PDGF-A expression were associated with elevation of blood pressure rather than a direct effect of angiotensin II. To further delineate the role of PDGF-A and elevated blood pressure, we assessed the level of PDGF-A and -B mRNA and protein in the wall of large as well as small arteries in the one-kidney, one-clip (1K1C) hypertensive rat, a non-renindependent model of hypertension. Fourteen days after renal artery stenosis, the thoracic aorta and both femoral arteries were collected from 1K1C rats (n ϭ 8) and uninephrectomized controls (n ϭ 8) and immediately processed for morphological measurement, immunohistochemistry, RT-PCR, and Western blotting. Systolic blood pressure was significantly elevated in hypertensive rats (202 Ϯ 26 mmHg) compared with control rats (122 Ϯ 7.9 mmHg) and was accompanied by arterial hypertrophy in both aorta and femoral arteries. The mRNA for PDGF-A chain was increased threefold in the thoracic aorta (P Ͻ 0.05) of 1K1C rats, whereas the message for PDGF-B was not significantly changed in hypertensive versus control animals. A higher staining of the intima-media was observed by using an anti-PDGF-A chain polyclonal antibody on paraffin-embedded sections. Western blot results indicated an ϳ2-fold increase in PDGF-A protein in aortic and femoral wall of the 1K1C rats. The results showed that both the mRNA and protein for PDGF-A chain are increased and well correlated with the blood pressure and wall area, suggesting a direct effect of elevated pressure on PDGF synthesis, which, in turn, may affect the onset and progression of vascular hypertrophy. hypertension; aorta; femoral artery; platelet-derived growth factors; hypertrophy HYPERTENSION IS ACCOMPANIED by vascular changes that vary according to the size and structure of each particular artery. These changes include the hypertrophy of large arteries (27, 41) and the inward eutrophic remodeling of arterioles (13, 28), whereas small arteries (internal diameter 150-250 µm) may undergo inward eutrophic or hypertrophic remodeling, depending on the type of hypertension (12, 16). The exact mechanisms and the factors affecting these vascular changes are only known in part. Lately, the involvement of growth factors in the processes of vascular growth and remodeling has been emphasized. Among them, plateletderived growth factor (PDGF) is of special interest for the autocrine regulation of protein synthesis (9) and growth (7) in smooth muscle cells. Large vessels from normotensive rats and humans constitutively express low levels of PDGF-A mRNA, mainly in the medial layer, whereas the PDGF-B chain mRNA is ...

. AT 1 receptor inhibition does not reduce arterial wall hypertrophy or PDGF-A expression in renal hypertension. Am. J. Physiol. Heart Circ. Physiol. 278: H613-H622, 2000.-To separate the role of ANG II from pressure in hypertrophy of the vascular wall in one-kidney, one-clip (1K1C) hypertension, experimental and shamoperated rats were given the AT 1 -receptor antagonist losartan (20 mg · kg Ϫ1 · day Ϫ1 ) or tap water for 14 days. Mean arterial pressure was elevated in both experimental groups compared with controls. Rats were anesthetized with pentobarbital sodium, and the thoracic aorta and carotid, small mesenteric, and external spermatic arteries were harvested and embedded in paraffin. Tissue sections were used for morphological analysis, immunohistochemistry for 5-bromo-2Ј-deoxyuridine (BrdU) and platelet-derived growth factor (PDGF)-AA, stereological measurements, and in situ hybridization with a 35 S-labeled riboprobe for PDGF-A mRNA. Elevated cross-sectional areas of thoracic, carotid, and small mesenteric artery in 1K1C rats were not reduced by losartan. The internal diameter of the external spermatic artery and microvascular density of the cremaster muscle were reduced in 1K1C rats. The number of BrdU-positive nuclei per cross section did not differ between 1K1C and control arteries. PDGF-A mRNA was elevated in the arterial walls of 1K1C rats compared with controls and was hardly changed by losartan. PDGF-A protein stained strongly in the media of 1K1C arteries and was not inhibited by losartan; it appeared in the adventitia of all aortas and carotid arteries. These observations demonstrate that effects of ANG II mediated through the AT 1 receptor are not necessary for hypertrophy of the vascular wall during 1K1C hypertension or expression of PDGF-A.one-kidney, one-clip hypertension; losartan; arterial pressure; angiotensin; platelet-derived growth factor DURING THE COURSE of hypertension, individual arteries adapt to mechanical and hormonal stresses through alterations in medial thickness and/or internal and external diameters, depending on the size and function of the particular blood vessel. The larger arteries increase wall cross-sectional area with the development of outward hypertrophy (30, 45). The smaller arterioles undergo a decrease in lumen size without an increase in wall area and/or rarefaction, the reduction in number of functional vessels (16,31,38). Lumen reduction in the absence of hypertrophy is termed ''inward, eutrophic remodeling.'' Both ANG II and pressure have been implicated as stimuli for the vascular changes associated with hypertension (4,9,18,30,45). ANG II is a hypertrophic (18) as well as hyperplastic stimulus (47) of vascular smooth muscle cells (VSMCs) and has been shown to induce platelet-derived growth factor (PDGF)-A chain expression (28). Recently, we have shown that vascular hypertrophy following chronic infusion of ANG II was entirely prevented when the blood pressure was kept from rising by the simultaneous administration of minoxidil (34). Pressure, like ANG II,...