An endothelial cell-derived growth factor.

Gajdusek, Corinne M.; DiCorleto, Paul E.; Ross, Russell; Schwartz, Stephen M.

doi:10.1083/jcb.85.2.467

Cited by 305 publications

(103 citation statements)

References 23 publications

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“…13,[22][23][24] This regulation is growth state dependent, with subconfluent cultures of endothelial cells stimulating VSMC growth and postconfluent cultures inhibiting VSMC growth. 12,[25][26][27][28] Similarly, perlecan and endothelial-derived HSPGs have been shown to be essential in inhibiting the neointimal response to vascular injury. 14,29 -31 Our study adds a new dimension to these results, demonstrating that the regulation of perlecan by mechanical strain is an important mechanism in altering endothelial paracrine inhibition of VSMC proliferation in response to changes in mechanical environment.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine TGF-β Signaling Pathway

Baker

Ettenson

Jonas

et al. 2008

Circulation Research

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Abstract-Mechanical forces are potent modulators of the growth and hypertrophy of vascular cells. We examined the molecular mechanisms through which mechanical force and hypertension modulate endothelial cell regulation of vascular homeostasis. Exposure to mechanical strain increased the paracrine inhibition of vascular smooth muscle cells (VSMCs) by endothelial cells. Mechanical strain stimulated the production of perlecan and heparan sulfate glycosaminoglycans by endothelial cells. By inhibiting the expression of perlecan with an antisense vector we demonstrated that perlecan was essential to the strain-mediated effects on endothelial cell growth control. Mechanical regulation of perlecan expression in endothelial cells was governed by a mechanotransduction pathway requiring autocrine transforming growth factor ␤ (TGF-␤) signaling and intracellular signaling through the ERK pathway.Immunohistochemical staining of the aortae of spontaneously hypertensive rats demonstrated strong correlations between endothelial TGF-␤, phosphorylated signaling intermediates, and arterial thickening. Further, studies on ex vivo arteries exposed to varying levels of pressure demonstrated that ERK and TGF-␤ signaling were required for pressure-induced upregulation of endothelial HSPG. Our findings suggest a novel feedback control mechanism in which net arterial remodeling to hemodynamic forces is controlled by a dynamic interplay between growth stimulatory signals from VSMCs and growth inhibitory signals from endothelial cells. Key Words: mechanical strain Ⅲ hypertension Ⅲ TGF-␤ Ⅲ heparan sulfate proteoglycans Ⅲ perlecan T he endothelium is a dynamic constituent of the vascular system that exerts remarkable control over diverse process such as hemostasis, inflammation, and the regulation of vascular tone. 1,2 In addition to interacting with blood constituents and circulating cells, the vascular endothelium is exposed to a distinct mechanical environment consisting of hemodynamic shear stress and mechanical stretch from blood pressure. As a result, endothelial cells are optimally situated as both sensors and effectors in the vascular remodeling process. An extensive body of scientific work supports the concept that vascular cells respond to their mechanical environment. 3,4 In vitro, shear stress and stretch stimuli regulate endothelial cell production of regulatory molecules including nitric oxide, 5 reactive oxygen species, 6 inflammatory cell adhesion molecules, 7 and extracellular matrix molecules. 8 Similarly, vascular smooth muscle cells (VSMCs) respond to mechanical stimuli by altering their expression of cell adhesion and extracellular matrix molecules 9 as well as increasing proliferation and migration. 10,11 An essential function of the intact endothelium is the paracrine regulation of the growth and phenotype of underlying VSMCs. Soluble heparan sulfate proteoglycans (HSPGs) are intimately involved in endothelial inhibition of VSMC proliferation. 12-14 These complex molecules are composed of a core protein covalently coup...

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Section: Discussionmentioning

confidence: 99%

Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine TGF-β Signaling Pathway

Baker

Ettenson

Jonas

et al. 2008

Circulation Research

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“…This causes release of the platelet-derived growth factor (PDGF) discovered by Ross and his coworkers, 14 which stimulates smooth muscle cells to proliferate and to secrete connective tissue matrix elements. Macrophages and endothelial cells have been recently shown 15 ' 16 to secrete growth factors. Thus, repeated episodes of endothelial damage and repeated bouts of smooth muscle cell replication can lead to the development of the "space-occupying lesion" we recognize as an atheroma.…”

Section: The Endothelial Injury Hypothesismentioning

confidence: 99%

Lipoproteins and atherosclerosis. A look back and a look ahead.

Steinberg¹

1983

Arteriosclerosis

290

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“…Four clones were isolated and kindly provided by Drs. C. Gajdusek and S. Schwartz (13), and the 6th clone was the generous gift of Dr. W. Laug (14). All cultures were grown to confluency in 60-mm dishes before use (15).…”

Section: Cell Culturementioning

confidence: 99%

Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activators.

Levin¹,

Loskutoff²

1982

The Journal of Cell Biology

370

112

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Cell extracts and conditioned media (CM) from cultured bovine aortic endothelial cells (BAEs) were fractionated by PAGE in the presence SDS, and plasminogen activator (PA) activity was localized by fibrin autography. Multiple molecular weight forms of PA were detected in both preparations. Cell-associated PAs had Mr of 48,000, 74,000, and 100,000 while secreted PAs showed Mr of 52,000, 74,000, and 100,000. A broad zone of activity (Mr 80,000-100,000) also was present in both cellular fractions. In addition, PAs of Mr 41,000 and 30,000 appeared upon prolonged incubation or repeated freezing and thawing of the samples, and probably represent degradation products of higher molecular weight forms. This complex lysis pattern was not observed when CM was subjected to isoelectric focusing. Instead, only two classes of activator were resolved, one at pH 8.5, the other at 7.6. Analysis of focused samples by SDS PAGE revealed that the activity at pH 8.5 resulted exclusively from the Mr 52,000 form; all other forms were recovered at pH 7.6. The activity of the Mr 52,000 form was neutralized by anti-urokinase IgG but was not affected by antitissue activator IgG indicating that it is a urokinaselike PA. The activities of the Mr 74,000-100,000 forms were not affected by anti-urokinase. They were blocked by antitissue activator suggesting that all the forms in this group were tissue-type PAs. The multiple forms of PA were differentially sensitive to inactivation by diisopropylfluorophosphate (DFP). Treatment of CM with 10 mM DFP for 2 h at 37 degrees C only partially inhibited the 52,000-dalton form. However, it completely inactivated the 74,000-dalton partially inhibited the 52,000-dalton form. However, it completely inactivated the 74,000-dalton PA. The activity of the Mr 100,000 form was not affected by this treatment, or by treatment with 40 mM DFP. Thus, cultured BAEs produce multiple, immunologically distinct forms of PA which differ in size, charge, and sensitivity to DFP. These forms include both urokinaselike and tissue-activator-like PAs. The possibility that one of these forms is a zymogen is discussed.

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An endothelial cell-derived growth factor.

Cited by 305 publications

References 23 publications

Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine TGF-β Signaling Pathway

Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine TGF-β Signaling Pathway

Lipoproteins and atherosclerosis. A look back and a look ahead.

Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activators.

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