Factors controlling growth and matrix production and matrix production in vascular smooth muscle and glomerular mesangial cell

Dubey, Raghvendra K.; Jackson, Edwin K.; Rupprecht, Harald; Sterzel, R.B.

doi:10.1097/00041552-199701000-00016

Cited by 85 publications

(83 citation statements)

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“…Key Words: adenosine deaminase Ⅲ adenosine kinase Ⅲ hypertension Ⅲ proliferation Ⅲ vascular disease S mooth muscle cells (SMCs) within conduit and resistance arteries are importantly involved in the pathophysiology of vascular remodeling induced by hypertension. 1 In this regard, SMC growth, both hypertrophic 1 and hyperplastic, 2,3 contributes to pathological structural changes within the vessel wall in spontaneously hypertensive rats (SHR). SMC growth is regulated by multiple factors.…”

mentioning

confidence: 99%

“…1 In this regard, SMC growth, both hypertrophic 1 and hyperplastic, 2,3 contributes to pathological structural changes within the vessel wall in spontaneously hypertensive rats (SHR).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…1 Under normal conditions, vascular SMC quiescence is maintained by a balance between vessel wall-derived and circulating growth inhibitors and growth promoters. 1 Disruption of the balanced generation of growth promoters and growth inhibitors under pathological conditions triggers a cascade of events leading to increased proliferation of SMCs and enhanced deposition of extracellular matrix proteins by SMCs. Therefore, endogenous factors that are generated by cells within the vessel wall and that inhibit SMC growth may play a major vasoprotective role, and decreased vascular levels of growth-inhibitory factors may contribute to vascular disease in hypertension.…”

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confidence: 99%

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Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Dubey¹,

Mi²,

Gillespie³

et al. 2001

ATVB

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Abstract-The objective of this investigation was to determine whether the regulation of extracellular adenosine levels by smooth muscle cells (SMCs) from conduit arteries (aorta) and resistance microvessels (renal arterioles) is different in spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto (WKY) rats. Basal extracellular adenosine levels were decreased in cultured aortic and arteriolar SHR SMCs, and the increase in extracellular adenosine levels induced by stimulation of the cAMP-adenosine pathway was less in aortic and arteriolar SHR SMCs. Extracellular adenosine levels were lower in SHR SMCs, however, even when the cAMP-adenosine pathway was inhibited with 3-isobutyl-1-methylxanthine. Inhibition of adenosine kinase with iodotubercidin and inhibition of adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl) adenine increased extracellular adenosine; however, only inhibition of adenosine deaminase equalized extracellular adenosine levels in SHR versus WKY SMCs. Membrane-disrupted SHR SMCs metabolized exogenous adenosine faster than WKY SMCs did, and this difference was abolished by inhibition of adenosine deaminase but not adenosine kinase. SHR SMCs demonstrated a greater proliferative response than WKY SMCs. This enhanced proliferative response was not blocked by adenosine per se or inhibition of adenosine kinase but was blocked by inhibition of adenosine deaminase and by 2-chloroadenosine (adenosine deaminase-resistant adenosine analogue). We conclude that dysregulation of extracellular adenosine levels exists in SHR SMCs, that this dysregulation is not due to a defect in the cAMP-adenosine pathway but rather to enhanced activity of adenosine deaminase, and that the dysregulation of extracellular adenosine mediates the enhanced proliferative response of SHR SMCs. Key Words: adenosine deaminase Ⅲ adenosine kinase Ⅲ hypertension Ⅲ proliferation Ⅲ vascular disease S mooth muscle cells (SMCs) within conduit and resistance arteries are importantly involved in the pathophysiology of vascular remodeling induced by hypertension. 1 In this regard, SMC growth, both hypertrophic 1 and hyperplastic, 2,3 contributes to pathological structural changes within the vessel wall in spontaneously hypertensive rats (SHR). SMC growth is regulated by multiple factors. 1 Under normal conditions, vascular SMC quiescence is maintained by a balance between vessel wall-derived and circulating growth inhibitors and growth promoters. 1 Disruption of the balanced generation of growth promoters and growth inhibitors under pathological conditions triggers a cascade of events leading to increased proliferation of SMCs and enhanced deposition of extracellular matrix proteins by SMCs. Therefore, endogenous factors that are generated by cells within the vessel wall and that inhibit SMC growth may play a major vasoprotective role, and decreased vascular levels of growth-inhibitory factors may contribute to vascular disease in hypertension.In this regard, it is conceivable that dysregulation of vascular adenosine levels in hyp...

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mentioning

confidence: 99%

“…1 In this regard, SMC growth, both hypertrophic 1 and hyperplastic, 2,3 contributes to pathological structural changes within the vessel wall in spontaneously hypertensive rats (SHR).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Dubey¹,

Mi²,

Gillespie³

et al. 2001

ATVB

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“…Osmotic pumps (ALZET minipumps) containing either vehicle or 2-ME were implanted for intravenous delivery of the vehicle or drug at a rate of 350 g·kg Ϫ1 ·day Ϫ1 . This dose was selected based on our previously published studies (13,31,33). After 14 days, the animals were euthanized and perfused fixed for morphometric analysis as described before (24).…”

Section: Separation Of Membrane Fractions From Whole Cell Lysatementioning

confidence: 99%

2-Methoxyestradiol blocks the RhoA/ROCK1 pathway in human aortic smooth muscle cells

Rigassi

Bozzolo

Lucchinetti

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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-2-Methoxyestradiol (2-ME), a metabolite of estradiol with little affinity for estrogen receptors, inhibits proliferation of vascular smooth muscle cells; however, the molecular mechanisms underlying this effect are incompletely understood. Our previous work shows that 2-ME inhibits initiation (blocks phosphorylation of ERK and Akt) and progression (reduces cyclin expression and increases expression of cyclin inhibitors) of the mitogenic pathway and interferes with mitosis (disrupts tubulin organization). Because the RhoA/ROCK1 pathway (RhoA ¡ ROCK1 ¡ myosin phosphatase targeting subunit ¡ myosin light chain) is involved in cytokinesis, herein we tested the concept that 2-ME also blocks the RhoA/ROCK1 pathway. Because of the potential importance of 2-ME for preventing/treating vascular diseases, experiments were conducted in female human aortic vascular smooth muscle cells. Microarray transcriptional profiling suggested an effect of 2-ME on the RhoA/ROCK1 pathway. Indeed, 2-ME blocked mitogen-induced GTP-bound RhoABC expression and membrane-bound RhoA, suggesting interference with the activation of RhoA. 2-ME also reduced ROCK1 expression, suggesting reduced production of the primary downstream signaling kinase of the RhoA pathway. Moreover, 2-ME inhibited RhoA/ROCK1 pathway downstream signaling, including phosphorylated myosin phosphatase targeting subunit and myosin light chain; the ROCK1 inhibitor H-1152 mimicked these effects of 2-ME; both 2-ME and H-1152 blocked cytokinesis. 2-ME also reduced the expression of tissue factor, yet another downstream signaling component of the RhoA/ROCK1 pathway. We conclude that 2-ME inhibits the pathway RhoA ¡ ROCK1 ¡ myosin phosphatase targeting subunit ¡ myosin light chain, and this likely contributes to the reduced cytokinesis in 2-ME treated HASMCs.2-methoxyestradiol; RhoA; ROCK1; myosin phosphatase targeting subunit; myosin light chain; cytokinesis 2-METHOXYESTRADIOL (2-ME) is an endogenous metabolite of estradiol that attenuates vascular smooth muscle cell (VSMC) proliferation, migration, and extracellular matrix synthesis (5,8,9) and reduces injury-induced neointima formation (4), cholesterol-induced atherosclerosis (9), monocrotaline-induced vascular thickening in pulmonary hypertension (9), and injuryinduced glomerosclerosis (9). Although 2-ME inhibits VSMC proliferation and is thus effective against multiple proliferative disorders (4, 9, 10), the mechanisms via which 2-ME mediates these actions remain incompletely understood.Our previously published work shows that in human aortic vascular smooth muscle cells (HASMCs) 2-ME inhibits cell proliferation in part by blocking initiation of the mitogenic pathway (4). Specifically, 2-ME inhibits phosphorylation of both ERK1/2 and Akt (Fig. 1), which turns off the mitogenic pathway by decreasing the expression and activity of cyclins. Indeed, we (4) found that 2-ME 1) blocks cell-cycle progression in both G0/G1 and in G2/M phases, 2) reduces cyclin D1 and cyclin B1 expression, 3) inhibits Cdk-1 and Cdk-2 activity, 4) reduc...

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Regulation of cell proliferation by the guanosine-adenosine mechanism: role of adenosine receptors

Jackson

Gillespie

2013

Physiol Rep

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A recent study (American Journal of Physiology-Cell Physiology 304: C406–C421, 2013) suggests that extracellular guanosine increases extracellular adenosine by modifying the disposition of extracellular adenosine (“guanosine-adenosine mechanism”) and that the guanosine-adenosine mechanism is not mediated by classical adenosine transport systems (SLC28 and SLC29 families) nor by classical adenosine-metabolizing enzymes. The present investigation had two aims: 1) to test the hypothesis that the “guanosine-adenosine mechanism” affects cell proliferation; and 2) to determine whether the transporters SLC19A1, SLC19A2, SLC19A3 or SLC22A2 (known to carrier guanosine analogues) might be responsible for the guanosine-adenosine mechanism. In the absence of added adenosine, guanosine had little effect on the proliferation of coronary artery vascular smooth muscle cells (vascular conduit cells) or preglomerular vascular smooth muscle cells (vascular resistance cells). However, in the presence of added adenosine (3 or 10 μmol/L), guanosine (10 to 100 μmol/L) decreased proliferation of both cell types, thus resulting in a highly significant (p<0.000001) interaction between guanosine and adenosine on cell proliferation. The guanosine-adenosine interaction on cell proliferation was abolished by 1,3-dipropyl-8-(p-sulfophenyl)xanthine (adenosine receptor antagonist). Guanosine (30 μmol/L) increased extracellular levels of adenosine when adenosine (3 μmol/L) was added to the medium. This effect was not reproduced by high concentrations of methotrexate (100 μmol/L), thiamine (1000 μmol/L), chloroquine (1000 μmol/L) or acyclovir (10,000 μmol/L), archetypal substrates for SLC19A1, SLC19A2, SLC19A3, and SLC22A2, respectively; and guanosine still increased adenosine levels in the presence of these compounds. Conclusion: The guanosine-adenosine mechanism affects cell proliferation and is not mediated by SLC19A1, SLC19A2, SLC19A3 or SLC22A2.

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Factors controlling growth and matrix production and matrix production in vascular smooth muscle and glomerular mesangial cell

Cited by 85 publications

References 0 publications

Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

2-Methoxyestradiol blocks the RhoA/ROCK1 pathway in human aortic smooth muscle cells

Regulation of cell proliferation by the guanosine-adenosine mechanism: role of adenosine receptors

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