In vivo and in vitro cellular changes in experimental hypertension: Electronmicroscopic and morphometric studies of aortic smooth muscle cells

Grünwald, J.; Robenek, Horst; Mey, Jörg; Hauss, W. H.

doi:10.1016/0014-4800(82)90091-0

Cited by 36 publications

(10 citation statements)

References 16 publications

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“…However, unknown stimuli occurring spontaneously in diabetes, hypertension, and hypercholesteremia result in qualitatively similar SMC alteration. For example, SMC cultured from diabetic 23 or hypertensive 22 rats and from hypercholesteremic rabbits 20 showed increased proliferation in vitro in addition to altered prostaglandin production, 21 collagen, 30 and glycosaminoglycan 1924 synthesis. Primary SMC cultures from human fatty streaks, but not from fully developed plaques, also showed an increased thymidine uptake.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, an increase in cell proliferation, as well as morphological and biochemical changes, have been demonstrated in SMC cultured from arteriosclerotic rabbits 19 " 21 and from hypertensive or diabetic rats. 22 " 24 Differences in SMC outgrowth after mechanical injury of the rabbit aorta have also been reported briefly. 25 We have extended this work in the studies reported here by quantifying SMC migration and proliferation in explant cultures and subcultivations after balloon injury of the rat aorta.…”

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confidence: 99%

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Intimal injury in vivo activates vascular smooth muscle cell migration and explant outgrowth in vitro.

Grünwald¹,

Haudenschild²

1984

Arteriosclerosis

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In vivo induced endothelial injury results in an intimal thickening, mainly caused by stimulation of smooth muscle cells (SMC), which migrate into, and proliferate in, the denuded intima. We evaluated the manifestation and persistence of this stimulus in several in vitro explant and growth assays using aortic explants from either balloon catheter-injured rats or from sham-operated controls. SMC outgrowth from control explants started 48 hours after explantation, became half-maximal after 96 hours, with 74% of the explants showing outgrowth. Explants from balloon-injured aortas showed SMC outgrowth within 24 hours, became half-maximal after 48 hours, with 92% of the explants showing outgrowth. An interval of 4 to 7 days between balloon injury and sacrifice was optimal for obtaining accelerated outgrowth, while a 1-day interval showed a weak stimulation and a 21-day interval had no such effect. The in vivo stimulated cells grew more rapidly, resulting in a greater colony size per explant, and they became temporarily serum-independent. Increased growth rate persisted up to the second subculture but returned to normal in subsequent passages. 2 Altered endothelial integrity is thought to expose the underlying SMC to stimuli that induce migration of the SMC through the internal elastic lamina to the intima, where they proliferate.34 Approximately 3 to 4 days after experimental injury, 56 activated or modulated SMC 7 ' 8 appear at the luminal surface and form an intimal thickening that displays many features of an atherosclerotic plaque.Cell culture techniques are now widely used to study the growth kinetics and morphology of SMC. 24 Differences in SMC outgrowth after mechanical injury of the rabbit aorta have also been reported briefly. 25 We have extended this work in the studies reported here by quantifying SMC migration and proliferation in explant cultures and subcultivations after balloon injury of the rat aorta. These studies show that SMC migration and proliferation in vitro are accelerated and enhanced in response to the in vivo injury. Furthermore, the in vivo stimulus renders the SMC temporarily serum-independent.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Intimal injury in vivo activates vascular smooth muscle cell migration and explant outgrowth in vitro.

Grünwald¹,

Haudenschild²

1984

Arteriosclerosis

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“…3 The increase may be caused by a recruitment of a subpopulation of more motile cells or by an enhancement of motility of all aortic SMC in response to hypertension. 8 The SMC from the hypertensive rat aortae also showed a greater growth potential, which was assessed in vitro m the presence of 10% FBS. The increased size of the primary colonies could be caused by both increased growth and migration.…”

Section: Discussionmentioning

confidence: 99%

Effects of hypertension on migration and proliferation of smooth muscle in culture.

Haudenschild¹,

Grünwald²,

Chobanian³

1985

Hypertension

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SUMMARY Migratory and proliferative characteristics of explanted rat aortic smooth muscle cells were studied in response to hypertension induced by 4 weeks of deoxycorticosterone-salt administration. Under low serum conditions (0.1% fetal bovine serum), over 80% of aortic medial explants from hypertensive rats yielded smooth muscle cell colonies after 8 days of culture while fewer than 10% of the control explants were positive. Time lapse video analysis of subsequent growth in the presence of 10% serum revealed that interdivision times of smooth muscle cells from hypertensive animals were significantly shorter than those in controls (p < 0.01). Significant differences in proliferative capacity of smooth muscle cells were evident, even after one subculture (p < 0.01). Comparison of these results with data from mechanical injury suggests that 4 weeks of deoxycorticosterone-salt hypertension can potentiate subsequent smooth muscle cell migration and growth in vitro to an extent similar to that observed with the combined effects of total endothelial denudation and wall distention by a balloon catheter. N our earlier studies on the effects of hypertension on the vascular wall, we found that smooth muscle cells (SMC) and blood-borne cellular elements, together with excessive extracellular matrix, were present in the aortic intima in young rats after 4 weeks of deoxycorticosterone (DOC)-salt hypertension.1 Similar intimal changes were observed in normotensive, aged rats.2 The leukocytes originated from the circulating blood, as indicated by the positions of white cells adherent to and between endothelial cells, while the subendothelial SMC appeared to have migrated from the media. 2The present study was designed to investigate the effects of hypertension on SMC by determining migration and growth properties of the selected cells migrating out of aortic explants. We have made use of an explant test that we developed for the assessment of migration of SMC in response to dilating and denuding balloon catheter injury.-1 This assay allows the use of tissue culture methods to study proliferative and mi-

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“…By freeze-fracture of second subculture SM C . Grunwald et al [58] found that SM C isolated from hypertensive rats were much larger and their G J more randomly distributed and covering a greater surface area of the cell than in SM C isolated from normotensive animals. If indeed an increase in G J is associated with hypertension and autorhythmicity, our observation of a decrease in gene expression for Cx43 in hypercholesterolemia may be associated with decreased cell-cell communication among vascular me dial SM C that may contribute to decreased vasorespon siveness.…”

Section: Cx43 Mrna In Smooth Muscle Cellsmentioning

confidence: 99%

Connexin43 Gene Expression in the Rabbit Arterial Wall: Effects of Hypercholesterolemia, Balloon Injury and Their Combination

Polacek

Bech²,

McKinsey³

et al. 1997

J Vasc Res

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The specialized functions of endothelium require intercellular communication between endothelial cells within the monolayer, and between endothelium and other cells present in the vessel wall. This is accomplished by a combination of paracrine soluble mediators and direct gap-junctional intercellular communication (GJIC) mediated by a family of connexin proteins. A prominent connexin expressed by vascular cells in vivo and in vitro is connexin 43 (Cx43). We have investigated the in vivo gene regulation of Cx43 in the context of vascular pathology, as a result of mechanical injury, hypercholesterolemia or both. The aortoiliac bifurcation in the rabbit was examined following three types of insult: (1) diet-induced hypercholesterolemia resulting in macrophage-rich fatty streak lesions, (2) mechanical, stretch-denudation injury resulting in intimal smooth muscle cell (SMC) proliferation and (3) mechanical injury superimposed on hypercholesterolemia resulting in a complex vascular lesion having characteristics of both interventions. The normal rabbit iliac artery expressed approximately equal levels of Cx43 mRNA in the medial SMC layers and in the endothelium. In hypercholesterolemia-induced atherosclerosis, Cx43 expression was most prominent in macrophage foam cells even though normocholesterolemic precursor monocytes did not express Cx43 mRNA. Antibodies directed specifically to Cx43 protein confirmed the expression of macrophage gap junction protein in these cells. Medial SMC in hypercholesterolemia exhibited less Cx43 than their normal counterparts in control animals. Mechanical injury in the absence of hypercholesterolemia resulted in intimal thickening in which Cx43 expression in the intimal SMC was equivalent to that in the subjacent medial SMC, both being approximately equivalent to normal uninjured rabbit medial SMC expression. Cell-specific expression of Cx43 in combined mechanical injury/hypercholesterolemia was similar to that observed in hypercholesterolemia alone: Cx43 upregulation in macrophages, while medial SMC were downregulated. Normo- and hypercholesterolemic alveolar macrophages of the lung and Kupffer cells of the liver did not exhibit induction of Cx43 mRNA, nor did macrophages isolated from peritoneal or bronchial lavage fluid of the same animals. This work extends our previous finding of Cx43 upregulation in human atherectomy tissue and demonstrates that atherosclerotic lesions in situ, in a controlled animal model of atherosclerosis, exhibit cell-specific changes in Cx43 gene expression. Changes in medial SMC migration, proliferation and phenotype, as well as enhanced interactions between adherent/infiltrating monocytes and endothelium may be related to modified GJIC pathways in the vessel wall.

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In vivo and in vitro cellular changes in experimental hypertension: Electronmicroscopic and morphometric studies of aortic smooth muscle cells

Cited by 36 publications

References 16 publications

Intimal injury in vivo activates vascular smooth muscle cell migration and explant outgrowth in vitro.

Intimal injury in vivo activates vascular smooth muscle cell migration and explant outgrowth in vitro.

Effects of hypertension on migration and proliferation of smooth muscle in culture.

Connexin43 Gene Expression in the Rabbit Arterial Wall: Effects of Hypercholesterolemia, Balloon Injury and Their Combination

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