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T J Resink

Publications and source records attributed to T J Resink.

At least 37 records · Page 2Linked to original sources
PubMed1993

Effects of peptide vasoconstrictors on vessel structure.

The peptide vasoconstrictors angiotensin II and endothelin-1, originally described as being derived exclusively from the plasma renin-angiotensin system and vascular endothelium, respectively, have been demonstrated to be produced independently of these sources. Local tissue angiotensin-generating systems are well documented and endothelin production has been demonstrated for a variety of nonendothelial cells, including vascular smooth muscle cells. There is increasing evidence that these locally produced vasoconstrictor peptides may contribute to blood vessel homeostasis, as well as the development of vascular pathologic conditions. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support this hypothesis. In addition to their vasoconstrictor properties, angiotensin II and endothelin-1 act as potent biologic effectors. In vitro, both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops in vascular smooth muscle cells. The activity of these feedback loops in vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The most well-established autocrine feedback loops of vascular smooth muscle cells are constituted by platelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of angiotensin II and endothelin-1. The effects of the peptide vasoconstrictors on the (auto-) regulated feedback loops are of long-term structural importance, since both vasoconstrictors (via autocrine growth modulators) may influence the composition of the extracellular matrix of vascular smooth muscle cells. This includes effects on the synthesis and secretion of thrombospondin, fibronectin, tenascin, etc. The secretion of extracellular matrix glycoproteins themselves and incorporation into extracellular matrix in vitro appear to be linked to the activity of the autocrine feedback loops: e.g., stimulation of thrombospondin mRNA results in secretion of the glycoprotein only in the concomitant presence of exogenous platelet-derived growth factor, whereas the expression of fibronectin and tenascin may be directed by transforming growth factor-beta. The influence of angiotensin II and endothelin-1 on vascular smooth muscle cell surface receptor expression may represent a secondary mode of action of these vasoconstrictor peptides. Endothelin-1, for instance, can rapidly down-regulate platelet-derived growth factor-alpha receptor mRNA and both angiotensin II and endothelin-1, via induction of transforming growth factor-beta, may interrupt the platelet-derived growth factor based autocrine feedback loop. In vivo, the highly complex interactions between local and systemic vasoconstrictor production, autoregulated feedback loops, and extracellular matrix (which also serves as a reservoir for growth and differentiation modulators) are central to vessel homeostasis.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin II↗
PubMed1993

Expression of soluble and insoluble fibronectin in rat aorta: effects of angiotensin II and endothelin-1.

This study has investigated the influence of the vasoconstrictor peptides angiotensin II (Ang II) and endothelin-1 (ET-1) on fibronectin expression by vascular smooth muscle cells (VSMC). In confluent, quiescent cultures of VSMC, Ang II and ET-1 elevated fibronectin mRNA levels in a time- and dose-dependent fashion. ET-1 and Ang II also induced a time-dependent expression of immunoreactive fibronectin in cultures of aortic organoids, and for both peptides the fibronectin immunoreactivity was most prominent within those medial smooth muscle cell layers close to the vessel lumen. Immunoprecipitation of biosynthetically labelled fibronectin elaborated by cultured VSMC revealed a predominant expression of soluble fibronectin in response to Ang II, whereas for ET-1 the newly synthesized fibronectin was predominantly incorporated into the extracellular matrix deposit of the cells. These findings indicate that Ang II and ET-1 may exert disparate effects on smooth muscle cell phenotype and migration.

Angiotensin II↗
PubMed1993

The renin-angiotensin system and extracellular matrix.

A hallmark of vascular disease is the inappropriate proliferative and synthetic behaviour of vascular smooth muscle cells. This phenotypically immature behaviour arises as a consequence of the myocytes undergoing phenotypic conversion and/or clonal proliferation of a "fetal" type of smooth muscle cell preexisting in the vessel wall. De-differentiation and initiation of proliferation is not only induced by endothelial desquamation and acute exposure of smooth muscle cells to platelet-derived mitogens, but also occurs in the uninjured blood vessel. Therefore normal components of the blood vessel are implicit in the pathological process. These include vasoconstrictor peptides, growth factor peptides and extracellular matrix molecules. In vitro and in vivo experimentation has indicated that while some of these compounds individually are only mild stimulators of smooth muscle proliferative metabolism, they may act synergistically to induce robust responses. Here we discuss the effects of the vasoconstrictor peptide angiotensin II, which can be locally generated within the vessel wall itself, on the expression of extracellular matrix molecules in vitro and in vivo. We focus on the angiotensin II-modulated expression of extracellular matrix glycoproteins, e.g. thrombospondin, tenascin, fibronectin and laminin.

Angiotensin II↗
PubMed1993

Acetylsalicylic acid, at high concentrations, inhibits vascular smooth muscle cell proliferation.

The growth of human smooth muscle cells in culture is inhibited by acetylsalicylic acid (ASA). In comparison to control, the proliferation of cells treated with 270 mg/L lysinmono(acetylsalicylate)/30 mg/L glycine was inhibited by 50-90% under different culture conditions. Cell numbers per well (control vs. treated) were as follows: (a) 470,500 +/- 55,890 vs. 24,750 +/- 4,030 (p < 0.002) after 6 days in the presence of 10% fetal calf serum (FCS), (b) 160,500 +/- 9,920 vs. 74,000 (p < 0.001) after 8 days in the presence of 10% human serum; and (c) 387,000 +/- 29,420 vs. 35,250 +/- 1,110 (p < 0.001) after 8 days in the presence of 5% FCS. Significant inhibition of growth by lysinmono(acetylsalicylate) at 90 mg/L was noted only for cultures grown with 10% FCS. Lower concentrations of this drug were ineffective under all culture conditions. Higher dosages of ASA, which would prevent not only platelet aggregation but also smooth muscle cell growth, may therefore be indicated in therapy of patients who undergo percutaneous transluminal coronary angioplasty (PTCA) or coronary artery transplantation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Peptide vasoconstrictors, vessel structure, and vascular smooth-muscle proliferation.

The peptide vasoconstrictors angiotensin II (Ang II) and endothelin-1 (ET-1), originally thought to derive exclusively from the plasma renin-angiotensin system and vascular endothelium, respectively, have been demonstrated to be produced independently of such sources. Local tissue angiotensin-generating systems are well documented, and endothelin production has been demonstrated for a variety of nonendothelial cells, including vascular smooth-muscle cells (VSMC). There is increasing evidence from in vitro studies that local production of these vasoconstrictor peptides may contribute to blood vessel homeostasis and the development of vascular pathologies. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support this hypothesis. In addition to their vasoconstrictor properties, Ang II and ET-1 act as potent biological effectors. In vitro, both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops in VSMC. The activity of these feedback loops in vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The best-recognized autocrine feedback loops of VSMC are constituted by platelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of Ang II and ET-1. Because both vasoconstrictors (via their induction of autocrine growth modulators) may influence the composition of the extracellular matrix of VSMC, the effects of the peptide vasoconstrictors on the (auto-) regulated feedback loops are of long-term structural importance. Ang II and ET-1 promote the synthesis and secretion of the glycoproteins thrombospondin, fibronectin, and tenascin.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Concerted effects of lipoproteins and angiotensin II on signal transduction processes in vascular smooth muscle cells.

Low-density (LDL) and high-density (HDL3) lipoproteins dose-dependently activate phosphoinositide turnover and elevate cytosolic free Ca2+ concentrations ([Ca2+]i) in cultured vascular smooth muscle cells (VSMCs) from either human (microarterioles and aorta) or rat (aorta) sources. High-performance liquid chromatography analysis of cell extracts revealed comparable spectra of inositol phosphate isomers generated in response to either LDL, HDL3, or angiotensin II (Ang II). Thus, lipoproteins and Ang II may use similar, if not identical, signal transduction pathways for the generation and metabolism of inositol phosphates and intracellular Ca2+ mobilization in VSMCs. When Ang II was added in combination with either LDL or HDL3, the phosphoinositide and [Ca2+]i responses of VSMCs were either equal to or even greater than the sum of the effects elicited by the agonists individually. This additivity/synergy between Ang II and the lipoproteins was not accompanied by alteration in the half-maximally effective dose requirements of VSMCs for either Ang II (approximately 2 nmol/L, with or without lipoproteins) or lipoproteins (approximately 50 micrograms/mL for LDL and HDL3, with or without Ang II). Neither short-term (up to 10 minutes) nor long-term (48 hours) exposure of VSMCs to lipoproteins caused desensitization of phospholipase C and intracellular Ca2+ mobilization responses to either Ang II or lipoproteins. Since constant exposure of VSMCs to lipoproteins is a physiological circumstance, and because elevation of [Ca2+]i and activation of phosphoinositide turnover are pivotal events for VSMC contraction and growth, we suggest that the low concentrations of lipoproteins in the vessel intima may play an important role in regulating the response of the vasculature to Ang II.

Angiotensin II↗
PubMed1993

Vascular smooth muscle cell calcium fluxes. Regulation by angiotensin II and lipoproteins.

This study examined 45Ca uptake, 45Ca efflux, and the distribution of exchangeable 45Ca in confluent, quiescent cultures of aortic smooth muscle cells (VSMCs) from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). These parameters were investigated under basal conditions and after addition of angiotensin II (Ang II) and low (LDL) and high (HDL) density lipoproteins. Basal 45Ca uptake was approximately 50% greater in VSMCs from SHRs (p < 0.005 versus WKY). Calcium antagonists (diltiazem or nifedipine) abolished this difference. The 45Ca uptake response to Ang II was approximately twofold greater in SHR than in WKY VSMCs (p < 0.05), and Ang II-induced increments of 45Ca uptake were weakly inhibited (by approximately 15-25%) by calcium antagonists. Lipoproteins also stimulated 45Ca uptake in VSMCs, and the apparent affinity of this process was approximately fivefold greater for LDL than for HDL. Calcium antagonists did not inhibit either LDL- or HDL-induced 45Ca uptake. SHR and WKY VSMCs did not differ with respect to 45Ca uptake induced by either LDL or HDL. The initial size of the slowly exchangeable pool of intracellular Ca2+ was approximately 35% greater in SHR VSMCs (p < 0.05 versus WKY). Ang II-induced mobilization of intracellular calcium (measured as the decrease in 45Ca content of the slowly exchangeable pool) was threefold greater in SHR VSMCs (p < 0.005 versus WKY). LDL and HDL marginally stimulated 45Ca efflux from this pool (< or = 20% above control) and to comparable extents in both SHR and WKY VSMCs.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1992

Volume-dependent regulation of sodium and potassium fluxes in cultured vascular smooth muscle cells: dependence on medium osmolality and regulation by signalling systems.

To identify ion transport systems involved in the maintenance of vascular smooth muscle cell volume the effects of incubation medium osmolality and ion transport inhibitors on the volume and 86Rb and 22Na transport in cultured smooth muscle cells from rat aorta (VSMC) have been studied. A decrease of medium osmolality from 605 to 180 mosm increased intracellular water volume from 0.6 to 1.3 microliters per 10(6) cells. Under isosmotic conditions, cell volume was decreased by ouabain (by 10%, P less than 0.005) but was not influenced by bumetanide, furosemide, EIPA and quinidine. These latter compounds were also ineffective in cell volume regulation under hypotonic buffer conditions. Under hyperosmotic conditions, cell volume was decreased by bumetanide (by approximately 7%, P less than 0.05) and by ethylisopropyl amiloride (by approximately 13%, P less than 0.005). Ouabain-sensitive 86Rb influx was decreased by 30-40% under hypoosmotic conditions. An increase in medium osmolality from 275 to 410 mosm resulted in an approximately eightfold increase in bumetanide-inhibited 86Rb influx and 86Rb efflux. The (ouabain and bumetanide)-insensitive component of 86Rb influx was not dependent on the osmolality of the incubation medium. However (ouabain and bumetanide)-insensitive 86Rb efflux was increased by approximately 1.5-2 fold in VSMC incubated in hypotonic medium. Ethylisopropyl amiloride-inhibited 22Na influx was increased by approximately sixfold following osmotic-shrinkage of VSMC. The data show that both Na+/H+ exchange and Na+/K+/2Cl- cotransport may play a major role in the regulatory volume increase in VSMC. Basal and shrinkage-induced activities of Na+/K+/2Cl- cotransport in VSMC were similarly sensitive to inhibition by either staurosporin, forskolin, R24571 or 2-nitro-4-carboxyphenyl N,N-diphenylcarbomate (NCDC). In contrast basal and shrinkage-induced Na+/K+/2Cl- cotransport were differentially inhibited by NaF (by 30 and 65%, respectively), suggesting an involvement of guanine nucleotide binding proteins in the volume-sensitive activity of this carrier. Neither staurosporin, forskolin, R24571 nor NCDC influenced shrinkage-induced Na+/H+ exchange activity. NaF increased Na+/H+ exchanger activity under both isosmotic and hyperosmotic conditions. These data demonstrate that different intracellular signalling mechanisms are involved in the volume-dependent activation of the Na+/K+/2Cl- cotransporter and the Na+/H+ exchanger.

Alkaloids↗
PubMed1992

Effects of endothelin-1 on vascular smooth muscle cell phenotypic differentiation.

Endothelin-1 (ET-1) produced by vascular endothelial cells has been proposed to act in a paracrine manner on adjacent smooth muscle cells (SMCs) in vivo, exerting a variety of short- and long-term effects. Although some of the in vitro ET-1-mediated effects are related to growth-promoting events, the physiological significance of these observations remains to be clarified. Reported discrepancies of the mitogenic potential of ET-1 may relate to differences in culturing conditions (submitogenic levels of serum in combination with ET-1). Because ET-1 has been implicated in proliferation of vascular SMCs (VSMCs) at sites of vascular injury, as well as pathological events during atherogenesis, a clarification of the mitogenic effects of ET-1 is important. This study demonstrates the possible autocrine role for ET-1 in the regulation of the vasculature, its influence on VSMC cell cycle, and autocrine and phenotypic regulation of VSMCs. Stimulation of quiescent VSMCs with a variety of peptides resulted in the secretion of biologically active ET-1 by VSMCs. In contrast to previous reports, long-term exposure (12-15 days) of VSMCs to ET-1 in nonmitogenic medium did not promote cycling of cells. On the contrary, ET-1 attenuated the cycling of VSMCs in the S and G2/M phases and interrupted progression through the cell cycle at late G1/early S phase. Subsequent to ET-1 exposure, VSMCs expressed increased levels of smooth muscle-specific alpha-actin. Therefore, autocrine-produced ET-1 may contribute to phenotypic differentiation of VSMCs.

Actins↗
PubMed1992

Oxidized low density lipoproteins stimulate phosphoinositide turnover in cultured vascular smooth muscle cells.

Atherogenesis is associated with alterations in the properties of different cell types, including monocytes/macrophages (foam cell formation), platelets (increased aggregation), endothelial cells (injury), and smooth muscle cells (SMCs) (lipid accumulation or foam cell formation). Oxidized low density lipoproteins (ox-LDL) play a key role in this vascular pathology. This study investigated the ability of ox-LDL to elicit chemical signaling events in cultured human vascular smooth muscle cells (VSMCs). Ox-LDL was found to stimulate phospholipase C-mediated phosphoinositide turnover in human VSMCs. This response occurred rapidly (within 1 minute) and at low concentrations of ox-LDL (half-maximal effective concentration, approximately 5 micrograms/ml). Ox-LDL-stimulated inositol phosphate accumulation in human VSMCs was inhibited by pretreatment of cells with phorbol 12-myristate 13-acetate and with compounds that elevate cyclic AMP or cyclic GMP. Ca2+ antagonists also blocked the effects of ox-LDL on phosphoinositide turnover. Inhibitors of receptor-endocytotic processes (including receptor clustering, cross-linking, and cytoskeleton-dependent internalization) effectively prevented ox-LDL-induced inositol phosphate generation. The data suggest that ox-LDL promotes phospholipase C-mediated phosphoinositide turnover in a manner analogous to that for other Ca(2+)-mobilizing hormones. The results also support an association between phosphoinositide turnover and receptor-mediated endocytosis. Prevention of the direct effects of ox-LDL on SMCs could prove an interesting therapeutic avenue for the prevention of atherosclerosis.

Calcium Channel Blockers↗
PubMed1992

Na(+)-K+ pump and Na(+)-K+ co-transport in cultured vascular smooth muscle cells from spontaneously hypertensive and normotensive rats: baseline activity and regulation.

OBJECTIVE: This paper examines the hypothesis that aberrations in vascular smooth muscle univalent ion transport systems play an important role in the pathogenesis of hypertension. DESIGN: Baseline Na(+)-K+ pump and Na(+)-K(+)-2Cl- co-transport activities and the regulation of these ion transport systems by angiotensin II and second messenger molecules have been studied in cultured aortic smooth muscle cells (VSMC) from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Ion transport was studied using isotopic univalent cations (86Rb and 22Na). RESULTS: Baseline Na(+)-K+ pump activity was comparable between SHR- and WKY-derived VSMC. Baseline Na(+)-K(+)-2Cl- and K(+)-Cl- co-transport activity as well as K+ leakage were significantly greater in SHR VSMC. Baseline Na(+)-K(+)-2Cl- co-transport was sensitive to inhibition by forskolin and ethyleneglycol-bis-(beta-amino ethylester)-N,N,N',N'-tetraacetic acid, whereas cyclic guanosine monophosphate and phorbol 12-myristate, 13-acetate had no effect. Angiotensin II-stimulated Na(+)-K(+)-2Cl- co-transport activity did not differ between WKY and SHR VSMC. Angiotensin II increased Na(+)-K(+)-pump activity to a significantly greater extent in SHR VSMC. The stimulatory effect of angiotensin II upon Na(+)-K+ pump activity was reduced under Na(+)-free buffer conditions and in the presence of the Na(+)-H+ exchange inhibitor, ethylisopropyl amiloride. Na(+)-K+ pump activity was also stimulated by the protein kinase C activator, phorbol 12-myristate, 13-acetate, and this was completely inhibited under Na(+)-free buffer conditions. CONCLUSIONS: SHR VSMC exhibit anomalous Na(+)-K(+)-pump and Na(+)-K(+)-2Cl- co-transport activities. The influence of these univalent ion transport systems upon cellular Na+ and Ca2+ homeostasis invoke their participation in the pathogenesis of hypertension.

Angiotensin II↗
PubMed1992

Vasoactive peptides and growth factors in the pathophysiology of hypertension.

A hallmark of vascular disease is the inappropriate proliferative and synthetic behavior of smooth muscle cells. This phenotypically immature behavior arises as a consequence of the myocytes undergoing conversion from a contractile to proliferative/secretory cell type. The stimulus invoked for this dedifferentiative process has been, until recently, endothelial desquamation and subsequent acute exposure of the smooth muscle cells to platelet-derived mitogens. Pathogenic conversion of myocytes occurs even in the absence of damage to the endothelium, however, and therefore normal components of blood vessels are implicit in this process. These include vasoconstrictor and growth factor peptides, as well as extracellular matrix molecules and associated compounds such as low-density lipoproteins. In vitro experimentation has indicated a number of compounds that, individually, are only mild stimulators of smooth muscle proliferative metabolism but which combine synergistically to induce robust responses. The enhanced proliferative metabolism exhibited by smooth muscle cells derived from the vessels of hypertensive animals, may arise as a consequence of their response to stimulation and/or to perturbation of the mechanisms involved in the inhibition of growth. In vitro experimental models such as the co-culture of smooth muscle and endothelial cells will facilitate definition of the influence of the endothelium on the processes that lead to smooth muscle conversion and modulated gene expression.

Angiotensin II↗
PubMed1991

Stimulation of autocrine platelet--derived growth factor AA-homodimer and transforming growth factor beta in vascular smooth muscle cells.

We have investigated the interrelationship between growth factors and vasoconstrictor peptides in terms of their possible paracrine/autocrine regulation of vascular smooth muscle cell differentiation/proliferation. Responses of quiescent cells from spontaneously hypertensive and Wistar-Kyoto rats to stimulation with a selected number of growth factors- and vasoconstrictor peptides were established (induction of mRNA as well as secretion of immunoreactive peptides). A single exposure of quiescent vascular smooth muscle cells to the vasoconstrictor peptides Angiotensin II and Endothelin-1 (10(-8) M each) resulted in a prolonged induction of platelet- derived growth factor A-chain and transforming growth factor beta transcripts (maximal at 5-6 hrs poststimulatory). The interrelationship between platelet- derived growth factor AA and transforming growth factor beta was investigated in experiments using the pure peptides individually for stimulation of mRNA and peptide secretion. Both growth factors enhanced their own and one anothers transcript expression. The results demonstrated that in spontaneously hypertensive rats, an established animal model of hypertension, the steady state balance of this set of growth factors may be disturbed. Defects involved may be attributable to alterations in the secretory machinery and/or amount of autocrine growth factor produced.

Angiotensin II↗
PubMed1991

A novel LLC-PK1 renal epithelial cell mutant impaired in in vivo down-regulation of cAMP-mediated hormonal response.

A novel "cAMP-resistant" variant of LLC-PK1 renal epithelial cells which is impaired in in vivo down-regulation of response following hormonal stimulation of adenylate cyclase (AC) is described. Compared to parental cells, the BIB27 mutant exhibited markedly higher in vivo activation of cAMP-dependent protein kinase (cAMP-PK) in response to the hormones salmon calcitonin (SCT) or [Arg8]-vasopressin (AVP) or the AC activator forskolin. The activation of cAMP-PK subsequent to agonist stimulation also persisted much longer in the mutant than in LLC-PK1 cells, although the cAMP-PK of BIB27 cells was normal in terms of both absolute levels and regulation by cAMP in vitro. Intracellular cAMP accumulation was also much higher in BIB27 than in LLC-PK1 cells following agonist stimulation. Production of cAMP could be detected in BIB27 cells even 12 h after treatment with AVP or SCT, whereas cAMP production in LLC-PK1 had returned to basal within 1 and 8 h, respectively. High levels of free cAMP-PK catalytic (C) subunit in BIB27 persisted even 12 h after hormone addition, meaning that the higher cAMP production in BIB27 did not result in the normal down-regulation of cAMP-PK C subunit levels. In vitro AC activity in BIB27 cell homogenates could be stimulated by hormones or receptor-independent agonists, but to a lesser extent than in LLC-PK1 cell homogenates. The SCT and AVP concentrations promoting half-maximal AC activation in BIB27 cells were about 10- and 3-fold higher than parental, respectively. BIB27 accordingly appeared to possess a mutation in AC responsible for the impairment of both in vitro response to agonists and the normal in vivo down-regulation processes following hormonal stimulation.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Angiotensin-induced growth related metabolism is activated in cultured smooth muscle cells from spontaneously hypertensive rats and Wistar-Kyoto rats.

Smooth muscle cells from spontaneously hypertensive rats (SHR) proliferate in culture faster than those isolated from sex- and age-matched Wistar-Kyoto (WKY) animals. There was no difference in the kinetics of S6 kinase activation in the two cultures, but later metabolic events associated with proliferation were stimulated earlier in SHR cells than in WKY, eg, activation of ornithine decarboxylase. Both cell types elaborated an extensive extra-cellular matrix in culture composed of a different blend of connective tissue macromolecules. Matrix material from SHR cells was more stimulatory to growth of WKY cultures than their own matrices. Angiotensin stimulated the growth and synthesis of extra-cellular matrix material in SHR more than in WKY derived vascular smooth muscle cell cultures.

Angiotensin II↗
PubMed1991

Platelet-derived growth factor A-chain homodimer stimulated growth of cultured smooth muscle cells from spontaneously hypertensive rats.

Vascular smooth muscle cells from spontaneously hypertensive rats (SHR) were growth stimulated when cocultured with bovine aortic endothelial cells whereas myocytes from normotensive, Wistar Kyoto rats (WKY) were growth inhibited. The responsiveness of cells from the two rat sources to the two homodimeric forms of platelet-derived growth factor (PDGF-AA or -BB) was different; SHR-derived cells responding equally well to both PDGF forms whereas cells from WKY responded to the B-chain homodimer only. The responses measured included S6 kinase activation, phospholipase C mediated phosphoinositide catabolism and cell growth. Saturation binding experiments using [125I]-labelled PDGF homodimers (AA or BB) indicated that smooth muscle cells from hypertensive rats possess similar numbers of cell-surface A-chain receptors (alpha subunits) as Swiss 3T3 cells which have been used to characterize the mitogenic effects of the two PDGF homodimeric forms. The differences in responsiveness of SHR vs WKY cells to PDGF-AA and to the influence of endothelial cells may reside in their differential expression of PDGF receptors.

Animals↗
PubMed1991

Induction of endothelin secretion by angiotensin II: effects on growth and synthetic activity of vascular smooth muscle cells.

Angiotensin II induces the synthesis and secretion of endothelin by cultured rat vascular smooth muscle cells. Previous studies demonstrate that angiotensin II also activates the synthesis of extracellular matrix-associated glycoconjugates (glycopeptides and proteoglycans) by cultured smooth muscle cells. Furthermore, in culture medium containing mitogen-depleted, plasma-derived serum (1.0%), angiotensin II stimulates the growth of rat smooth muscle cells. Therefore, the influence of endothelin-1 (ET-1) on the growth and matrix elaboration by cultured rat smooth muscle cells was studied to assess its contribution to the stimulatory activity of angiotensin II. In quiescent cultures of smooth muscle cells, no stimulation of the incorporation of [3H]thymidine into DNA by ET-1 was apparent, even at maximal doses (10(-7) M). Under the same conditions, the synthesis of extracellular matrix glycoconjugate material was not enhanced by ET-1, unlike angiotensin II. In cultures maintained in medium containing 1.0% plasma-derived serum, ET-1 was incapable of stimulating either proliferation or incorporation of [3H]thymidine into DNA whereas angiotensin II stimulated both activities. ET-1, however, did induce the expression of growth factor and thrombospondin genes in quiescent smooth muscle cultures. The data suggest that growth stimulation of smooth muscle cells by angiotensin II does not occur as a consequence of stimulated ET-1 production.

Angiotensin II↗