[Participation of urokinase in cell migration caused by growth factors].
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Animals↗
Biomedical subjects
A Bobik
Publications and source records attributed to A Bobik.
[Regulation of inositol-1,4,5-triphosphate receptor by G(i)-protein].
The pertussis toxin (PT) inhibits thrombin-induced mobilising of Ca2+ but does not affect formation of inositol-1, 4, 5-triphosphate (IPh3). The latter being related to Gi and G0, the possibility of a direct effect of these proteins on the IPh3-induced release of Ca2+ from sarcoplasmic reticulum, was studied. The data obtained suggest existence of an association of the Gi3 protein with the IPh3-P on the sarcoplasmic reticulum membrane, as well as a direct modulation by the Gi protein of the Ca2+ release from intracellular stores.
Animals↗
Vascular types I and II transforming growth factor-beta receptor expression: differential dependency on tyrosine kinases during induction by TGF-beta.
Recent evidence indicates that the type II transforming growth factor-beta (TGF-beta) receptor (TbetaRII) is a serine-threonine-tyrosine kinase. However, the significance of its tyrosine kinase is unclear. We investigated in vascular smooth muscle cells the effects of tyrosine kinase inhibition on the expression of TGF-beta receptor types I (ALK-5) and II (TbetaRII) mRNA, induced by TGF-beta1. TGF-beta1 elevated ALK-5 mRNA levels 5-fold; essentially similar TGF-beta1-dependent elevations were observed with growth factors, PDGF-BB and FGF-2. The tyrosine kinase inhibitor genistein abolished these TGF-beta1 and growth factor responses. TGF-beta1 also elevated TbetaRII mRNA levels which were not inhibited by genistein. We conclude that tyrosine kinases participate in defining how cells respond to TGF-beta.
Activin Receptors, Type I↗
Inhibitory effects of tranilast on expression of transforming growth factor-beta isoforms and receptors in injured arteries.
Tranilast (N(3,4-dimethoxycinnamoyl)anthranilic acid), an agent which in cell culture inhibits transforming growth factor-beta (TGF-beta) secretion and antagonises the effects of TGF-beta and platelet-derived growth factor (PDGF) on cell migration and proliferation, has been reported to reduce the incidence of restenosis after angioplasty in angiographically validated human clinical trials. We investigated in a rat model of balloon angioplasty whether tranilast's effects in vivo could be attributed to inhibition of expression of TGF-beta and/or its receptor types. Using a standardised reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we examined the effects of three doses of tranilast (25, 50 and 100 mg/kg) on the expression of two TGF-beta isoforms, the types I and II TGF-beta receptors and two putative TGF-beta responses, induction of integrins alpha(v) and beta3 mRNA, 2 h after oral administration and 26 h after vessel injury. Tranilast attenuated in a dose-dependent and reversible manner the injury-induced increases in mRNA levels encoding TGF-beta1, TGF-beta3, two type I TGF-beta receptors ALK-5 and ALK-2, and the type II receptor TbetaRII. At the highest dose mRNA levels encoding TGF-beta1 and TbetaRII were attenuated to levels approaching or below those observed in uninjured vessels. Messenger RNAs encoding TGF-beta3, ALK-5 and ALK-2 were all attenuated by between 70 and 74% (all P < 0.05). Tranilast also attenuated in a reversible manner the elevations in mRNA levels for integrins alpha(v) and beta3 observed after vessel injury, by 90 and 72%, respectively. We also investigated, in cultured smooth muscle cells derived from injured carotid arteries, the extent to which tranilast (300 mg/l) attenuated any increases in expression of type I and type II receptors stimulated by PDGF-BB and TGF-beta1, growth factors implicated in smooth muscle cell migration and proliferation in injured vessels. Increases in mRNA levels of the type I receptors ALK-5 and ALK-2 induced by PDGF-BB and TGF-beta1 were almost completely prevented by tranilast. Tranilast also prevented the PDGF-BB induced increases in TbetaRII but only partially inhibited the TGF-beta1 induced upregulation of TbetaRII. We conclude that tranilast can inhibit transcriptional mechanisms associated with the upregulation of TGF-beta and its receptor types in balloon catheter injured vessels. It is possible that these mechanisms contribute to its ability to reduce the frequency of restenosis after angioplasty.
Angioplasty, Balloon↗
Heterotrimeric Gi protein is associated with the inositol 1,4,5-trisphosphate receptor complex and modulates calcium flux.
In vascular smooth muscle, pertussis toxin (PT) inhibits thrombin-induced Ca2+ release by a mechanism independent of its effect on IP3 formation. Thus, the possibility of a direct role of G alpha i proteins in regulating IP3-sensitive Ca2+ release was investigated by examining whether G alpha i proteins are associated with the IP3 receptor complex. Purified microsomal membranes were prepared and separated by sucrose density gradient centrifugation. The relative density of [3H]-IP3 binding sites between the microsomal fractions was inversely related to the distribution of the plasma membrane marker. The relative distribution of G alpha i3 determined by immunoblotting was closely correlated with the density of [3H]-IP3 binding. Levels of G alpha i2 were more evenly distributed with highest levels present in plasma membrane-enriched fractions. IP3 receptor immunoprecipitated from triton-solubilized microsomal membranes contained G alpha i3 immunoreactivity. To determine whether G alpha i proteins influence IP3-induced Ca2+ release, the effect of PT on Ca2+ release from digitonin-permeabilized cell suspensions using Fluo-3 was examined. Exposure to PT (0.1 microgram/ml, 5 min) attenuated the initial rate of IP3 (1 microM)-induced Ca2+ release. Together, these findings are consistent with the hypothesis that a heterotrimeric G alpha i protein directly regulates IP3-dependent Ca2+ release.
Adenosine Diphosphate Ribose↗
Transforming growth factor-beta and receptor tyrosine kinase-activating growth factors negatively regulate collagen genes in smooth muscle of hypertensive rats.
Previous studies have suggested that differences in vascular smooth muscle cell (VSMC) proliferative responses between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats can be attributed to transforming growth factor-beta (TGF-beta) actions. Because vascular collagen content is reported to be lower in SHR than in WKY rats, in this study we investigated in cell culture whether the differences in collagen content might also be attributed to differential actions of TGF-beta on VSMCs from the two strains. Exposure of VSMCs from WKY to the TGF-beta isoforms -beta1, -beta2, or -beta3 induced rapid, transient elevations in mRNAs encoding collagens alpha1(I), alpha2(I), and alpha1(III); maximum increases were apparent by 2 hours and ranged from twofold [collagen alpha1(III)] to ninefold [collagen alpha1(I)]. Thereafter they returned to near basal levels. When VSMCs from SHR were exposed to these TGF-beta isoforms, only reductions in collagen mRNA levels were observed, persisting for 24 hours. Basic fibroblast growth factor and epidermal growth factor, factors known to stimulate production of the TGF-beta1 isoform in VSMCs, also induced a pattern of gene responses similar to those induced by the TGF-beta isoforms in VSMCs from SHR and WKY rats. The simultaneous presence of TGF-beta did not affect the time course or magnitude of the changes in collagens alpha1(I), alpha2(I), or alpha1(III) mRNA levels in SHR or WKY VSMCs. Examination of the induction of c-myc mRNA and immunoreactive oncoprotein content indicated that c-myc is a likely contributor to the downregulation of the collagen gene activity in both SHR and WKY VSMCs despite the differential regulation of its mRNA by TGF-beta1 in the two VSMC lines. Together these data suggest that in VSMCs from SHR, a number of gene responses to TGF-beta, in addition to cell proliferation, appear to be abnormal compared with WKY rats, and the lower than normal collagen levels observed in the vasculature of SHR may be in part due to abnormalities in TGF-beta responsiveness.
Animals↗
Sympatho-adrenal mechanisms regulating cardiovascular hypertrophy in primary hypertension: a role for rilmenidine?
OBJECTIVE: Overactivity of the sympatho-adrenal system has long been considered a major factor contributing to blood pressure elevation in primary hypertension in humans and experimental animals. Our aim has been to elucidate its role in the development of cardiovascular hypertrophy in hypertensives. METHODS: Two studies have been performed in spontaneously hypertensive rats (SHR). One involved irreversible inhibition of the sympatho-adrenal system in newborn SHR using a sympathectomy procedure combined with prolonged alpha1-adrenoceptor blockade. The other involved reversible, long-term inhibition of the sympatho-adrenal system in young but mature SHR, by treatment with rilmenidine, a centrally active antihypertensive agent interacting with imidazoline receptors. Their effects on cardiovascular structure were examined. RESULTS: Sympathectomy plus alpha1-adrenoceptor blockade prevented the development of cardiac and vascular hypertrophy in adolescent SHR and these effects were maintained later in life. Rilmenidine administered to older (9-week) SHR also attenuated cardiac hypertrophy, abolished perivascular fibrosis associated with the intramyocardial vessels, and normalized vessel structure in the richly sympathetically innervated mesenteric vasculature. These effects were only partially related to the level of blood pressure reduction. CONCLUSIONS: Inhibition of the sympatho-adrenal system not only reduces blood pressure to normotensive levels in SHR but also has beneficial effects on cardiovascular structure, potentially reducing risk factors for cardiac and renal abnormalities frequently seen in long-term hypertensives. Therapeutically, these effects are likely to be achieved with rilmenidine.
Adrenal Glands↗
Urokinase plasminogen activator induces smooth muscle cell migration: key role of growth factor-like domain.
We defined the role of urokinase plasminogen activator (uPA) and its growth factor-like domain (GFD) in stimulating smooth muscle cell (SMC) migration. Recombinant uPA (r-uPA) stimulated migration approximately 3-fold whilst the recombinant uPA mutant containing an altered GFD (r-uPAmut) was ineffective. Both uPA variants bound to the same high affinity receptor in a competitive manner. FGF-2- and PDGF-BB-induced migration was also dependent on uPA, their effects being antagonized by addition of a uPA-neutralizing antibody or the r-uPAmut. Thus r-uPA is chemotactic for SMC and stimulation of cell migration by PDGF-BB and FGF-2 is dependent on uPA. The GFD of uPA is essential for its chemotactic effects.
Amino Acid Sequence↗
Angiotensin-converting enzyme inhibition abolishes medial smooth muscle PDGF-AB biosynthesis and attenuates cell proliferation in injured carotid arteries: relationships to neointima formation.
BACKGROUND: ACE inhibitors can attenuate the development of intimal fibrocellular lesions after balloon catheter vessel injury, but the mechanisms responsible are unknown. METHODS AND RESULTS: To evaluate how basic fibroblast growth factor (FGF-2) and the platelet-derived growth factor (PDGF) isoforms are affected by ACE inhibition in injured rat carotid arteries in relation to smooth muscle cell (SMC) proliferation, we examined the effects of oral perindopril on FGF-2 and PDGF isoform levels in carotid arteries 2 days after balloon catheter injury. [3H]Thymidine incorporation into medial and intimal SMCs was also assessed. Uninjured vessels contained two forms of FGF-2, with molecular weights of 18 and 22 kD, and PDGF-AA. Two days after injury, FGF-2 and PDGF-AA levels were markedly reduced, but high levels of PDGF-AB became apparent when the SMCs were proliferating. Perindopril completely abolished the biosynthesis of PDGF-AB but had little effect on residual FGF-2. This was accompanied by a 25% reduction in medial SMC proliferation. Neointimal cell proliferation 10 days after injury was unaffected by perindopril, although neointima size was reduced by 30%. Commencing perindopril treatment 4 days after the injury confirmed that early events associated with effects on medial SMCs were the major contributors to the attenuated neointimal lesions. CONCLUSIONS: The ability of ACE inhibitors such as perindopril to attenuate neointima formation and growth in balloon catheter-injured rat carotid arteries is dependent on early events in the media, the inhibition of SMC PDGF-AB biosynthesis and attenuation of proliferation. Neointima formation in similarly injured vessels containing SMCs that are either unresponsive to PDGF-AB or exhibit an ACE-independent profile of growth factor biosynthesis responses may account for the ineffectiveness of ACE inhibition in some species.
Angiotensin-Converting Enzyme Inhibitors↗
Vascular growth responses in SHR and WKY during development of renal (1K1C) hypertension.
Intrinsic differences between vascular smooth muscle cells (VSMC) in normotension and genetic hypertension may account for the exaggerated growth response often observed in the hypertensive vasculature. To test this hypothesis, in this study we compared the vascular growth response of the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) following induction of one kidney, one clip (1KlC) renal hypertension. SHR and WKY rats were uninephrectomized and renal hypertension (RH) induced using silver clips of 0.22 and 0.24 mm width. Four weeks later, vessel and VSMC growth were assessed in small mesenteric arteries. The systolic blood pressure (SBP) in the RH animals was significantly higher than in uninephrectomised controls, in RH-SHR with a 0.24 mm clip SBP averaged 215 +/- 4 mm Hg and in RH-WKY with a 0.22 or 0.24 mm clip the SBPs averaged 214 +/- 5 mm Hg and 190 +/- 2 mm Hg, respectively. For the same SBP, there were no differences in medial cross-sectional areas of the small mesenteric arteries between RH-SHR and RH0.22-WKY, which averaged 1.73 +/- 0.19 x 10(4) microm2 and 1.66 +/- 0.15 x 10(4) microm2, respectively. Likewise, the number of VSMCs (within a precise anatomical site of the mesenteric vasculature) were not different between the RH-SHR and the RH0.22-WKY with VSMC number 7.6 +/- 0.8 x 10(4) cells and 6.9 +/- 0.4 x 10(4) cells, respectively. In the RH0.22-WKY vascular growth responses were generally unchanged compared with the RH0.24-WKY except for a further increase in the incidence of polyploid cells. In conclusion, the results of this study demonstrate that smooth muscle cells of the SHR are not hyperresponsive to all growth-promoting stimuli. Taken together with previous observations, it appears that sustained activity of the renin-angiotensin system may be required for exaggerated vascular growth responses in SHR.
Animals↗
Role of angiotensin II in early cardiovascular growth and vascular amplifier development in spontaneously hypertensive rats.
OBJECTIVE: To examine the role played by angiotensin II (AII) in the development of prehypertensive vascular hypertrophy in the spontaneously hypertensive rat (SHR) and to determine whether normalization of prehypertensive vascular hypertrophy attenuates the development of hypertension. DESIGN: Male SHR and Wistar-Kyoto (WKY) rats were treated from age 10 days until age 6 weeks with perindopril, an angiotensin converting enzyme (ACE) inhibitor, or with losartan, a type 1 AII receptor antagonist. METHODS: At termination of treatment, or 8 weeks after cessation of treatment, vascular growth was assessed by measurement of hindquarter resistance properties and of the medial cross-sectional area of first-order mesenteric arteries. The growth of the heart was assessed by measurement of the left ventricle:body weight ratio. RESULTS: Perindopril and losartan treatment of SHR and WKY rats led to a heterogeneous response in the vasculature, resulting in a reduction in perfusion pressures at maximum dilatation and constriction in the hindquarter vasculature but no significant change in medial cross-sectional area of small mesenteric arteries. Neither perindopril nor losartan treatment affected the growth of the left ventricle in the SHR. After the cessation of treatment the development of hypertension in the losartan- and perindopril-treated SHR did not differ from that in controls. CONCLUSION: These results suggest that AII, acting via angiotensin type 1 receptors, plays an important role in determining the early post-natal reactivity of the hindquarter vasculature but not the medial cross-sectional area of the mesenteric vasculature, which implies that different growth regulatory mechanisms are operating in the two vascular beds. The lack of effect in some vascular beds, together with the lack of effect on the heart, may account for the absence of a persistent effect on the blood pressure.
Angiotensin II↗
Effects of intracellular Ca2+ chelating on noradrenaline release in normoxic and anoxic hearts.
1. Ischaemia and anoxia induce excessive noradrenaline (NA) release in the heart by a mechanism independent of both nerve activity and extracellular Ca2+. The present study was designed to examine the potential role of intracellular Ca2+ mobilization in anoxic NA release in the heart by chelating intracellular free Ca2+. 2. In normoxic hearts, preloading with an intracellular free Ca2+ chelator (BAPTA) reduced neuronal NA release by 65%, confirming the effectiveness of the loading protocol. Release of NA independent of nerve activity occurred in hearts subjected to a 40 min period of anoxic, substrate-free and nominal Ca(2+)-free perfusion. Loading hearts with BAPTA prior to anoxia failed to reduce NA overflow (1561 +/- 147 vs 1496 +/- 206 pmol/g over 40 min). Infusion with BAPTA (20 mumol/L) during the first 25 min of the anoxic period reduced the quantity of anoxic NA release by approximately 25% from 2013 +/- 124 to 1476 +/- 207 pmol/g (P < 0.05). 3. Our results confirm that anoxic NA release is predominantly a Ca(2+)-independent process with Ca2+ mobilization from endogenous storage playing only a minor contributing role.
Animals↗
Inhibition of protein tyrosine kinases attenuates increases in expression of transforming growth factor-beta isoforms and their receptors following arterial injury.
Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in neointima formation in mechanically injured vessels and in restenosis after angioplasty. To further understand the significance of TGF-beta s in neointima formation, we examined the temporal expression of three TGF-beta isoforms (-beta 1, -beta 2, and -beta 3), their receptors (ALK-2, ALK-5, and T beta RII), and two putative TGF-beta responses (elevations in alpha v and beta 3 integrin mRNAs) in balloon catheter-injured rat carotid arteries and their dependency on tyrosine kinase activity. Using a standardized reverse transcriptase-polymerase chain reaction assay optimized to estimate mRNA levels, we observed distinct patterns of mRNA regulation for TGF-beta 1, -beta 2, and -beta 3 during the 48 hours immediately after injury, which were localized to the vessel's media. TGF-beta 1 mRNA increased 10-fold during this time while TGF-beta 3 mRNA also increased almost 2-fold. There were also increases in mRNAs encoding the TGF-beta type I receptors ALK-5 and ALK-2, as well as the type II receptor (T beta RII). Eight hours after the injury, mRNA levels for ALK-2 and ALK-5 were on average 2-fold higher; mRNA encoding the type II receptor increased approximately 3-fold by 24 hours. There were also associated increases in TGF-beta 1, TGF-beta 3, ALK-5, and T beta RII immunoreactive peptide levels. Peak increases in mRNAs for integrins alpha v and beta 3 averaged approximately 2-fold and 2.5-fold, respectively. Perivascular administration of the tyrosine kinase inhibitor genistein at the time of vessel injury markedly (> 85%) inhibited elevations in mRNAs encoding TGF-beta 1, TGF-beta 3, T beta RII, and the two integrins alpha v and beta 3, while application of its inactive chemically similar homologue daidzein did not prevent the injury-induced elevations in mRNA levels. Since the increases in integrins alpha v and beta 3 mRNA could be theoretically attributed to TGF-beta actions despite being dependent on tyrosine kinase activity, we examined whether the observed elevations in integrins alpha v and beta 3 were due to TGF-beta 1 secretion, using cultured rat carotid artery smooth muscle cells. TGF-beta 1 neutralizing antibodies specifically inhibited elevations in integrins alpha v and beta 3 mRNAs due to platelet-derived growth factor-BB and fibroblast growth factor-2. We conclude that multiple components of the TGF-beta system in vessels are activated following injury and influence expression of integrin receptors important for smooth muscle cell migration. Activation of the TGF-beta system appears to be highly dependent on tyrosine kinases.
Activin Receptors, Type I↗
Role of Ca2+ in metabolic inhibition-induced norepinephrine release in rat brain synaptosomes.
Ischemia and simulated ischemic conditions induce enhanced release of norepinephrine (NE) in the brain and the heart. Although studies with neuronal preparations demonstrated a rise in [Ca2+]i under energy-depleted conditions, such release of NE in the heart appears to be predominantly Ca2+ independent. Since Ca2+ overload occurs in ischemia or energy depletion and since a rise in [Ca2+]i triggers exocytosis without membrane depolarization, we tested the possibility, using brain synaptosomes, that increased NE release could be, at least in part, a consequence of raised [Ca2+]i. Brain synaptosomes were incubated with Krebs-Henseleit medium, and ischemia was mimicked by treatment with metabolic inhibitors. NE content in incubation medium (supernatant) and synaptosomes was analyzed chromatographically. Treatment with metabolic inhibitors reduced ATP content by 75% and increased [Ca2+]i by more than fourfold within minutes. Metabolic inhibition elicited NE release, which started within 10 minutes and reached a maximum after 30 minutes, with a corresponding 55% reduction in synaptosomal NE content after 40 minutes. NE release, together with a marked increase in [Ca2+]i, was also induced in energy-depleted synaptosomes by Ca2+ repletion after incubation with the Ca(2+)-free medium. Effects on NE release of various interventions to prevent Ca2+ overload were tested. Omission of Ca2+ from the incubation medium or loading synaptosomes with the Ca2+ chelator BAPTA-AM (20 and 100 mumol/L) prevented NE release, indicating a Ca(2+)-dependent mechanism. Inhibition of Ca2+ channels with omega-conotoxin, cadmium, or nifedipine had no effect on NE release during energy depletion. In contrast, nickel and 3,4-dichlorobenzamil, Na(+)-Ca2+ exchange inhibitors, dose-dependently inhibited NE release. In conclusion, this study provides evidence that under energy-depleted conditions, Ca2+ overload in synaptosomes of noradrenergic neurons from the brain is an important mechanism for the enhanced release of NE and that a reversal of Na(+)-Ca2+ exchange may be the key pathway leading to intraneuronal Ca2+ overload.
Animals↗
Vascular smooth muscle cells express multiple type I receptors for TGF-beta, activin, and bone morphogenetic proteins.
Vascular smooth muscle cells (VSMCs) are known to produce activins, bone morphogenetic proteins and transforming growth factor-betas (TGF-betas). To determine whether these TGF-beta superfamily members exert autocrine effects on VSMCs we examined whether specific type I receptors (ALKs) for such peptides were expressed by the cells. RNA from both quiescent or growth-factor-activated VSMCs was reverse transcribed then cDNAs encoding ALK-2, ALK-3, ALK-5, and ALK-6 were amplified and characterised using specific PCR primers. All four ALK mRNAs were abundantly expressed. The ALK-5 fragment harbored a deletion of 12 nucleotides, removing 4 extracellular amino acids (Gly-Pro-Ser-Val) adjacent to its transmembrane domain. This deletion, which may arise from anomalous splicing of heteronuclear RNA, is likely to influence formation of the ALK-5:type II receptor complex through conformational changes associated with removal of a putative hinge region containing proline. Our finding that multiple ALKs are expressed by VSMCs would account for the multiplicity of effects TGF-beta peptides exert on these cells.
Activin Receptors, Type I↗
Regulation and role of urokinase plasminogen activator in vascular remodelling.
1. Urokinase plasminogen activator (uPA) is produced and secreted by multiple vascular cell types, thus influencing the processes and the extent to which the vasculature is remodelled during the development of the intima or a neointima and during hypertrophy and angiogenesis. 2. Urokinase plasminogen activator mRNA expression is up- and down-regulated by growth factors, cytokines and steroids. Urokinase plasminogen activator is secreted as a single chain inactive form that may be proteolytically converted to active or inactive forms. Targeting of proteolytic activity may occur via focalized expression of uPA and its cell surface receptors (uPAR). Proteolytic activity is also controlled through the often co-ordinated expression of specific inhibitors. 3. A proteolytic cascade involving uPA provides its major role in tissue remodelling through the primary degradation of extracellular matrix and secondarily through the activation of transforming growth factor-beta or release from the matrix of basic fibroblast growth factor. In addition, uPA secreted by growth factor-stimulated vascular cells may contribute to the chemotactic and mitogenic responses ascribed to the growth factor and recent evidence strongly suggests that uPA has direct biological actions on vascular cells. 4. The cell surface binding of uPA via its growth factor-like domain to uPAR localizes and activates the protease, but may also initiate transmembrane signalling of biological responses, including migration/invasion and proliferation. As the uPAR lacks intracellular signalling domains, the signals may be transduced via interactions between uPA/uPAR and more classical signalling receptors. The mechanism by which uPA may be involved in cell signalling is yet to be elucidated.
Arteriosclerosis↗
Regulation and interactions of transforming growth factor-beta with cardiovascular cells: implications for development and disease.
1. Transforming growth factors-beta (TGF-beta) are multifunctional proteins that regulate cell growth, differentiation, migration and extracellular matrix production and have an important role in embryonic development and tissue remodelling. 2. The diverse biological actions of TGF-beta are elicited following their interaction with type I and type II TGF-beta receptors, both of which are transmembrane serine/threonine kinases, suggesting an important role for protein phosphorylation in the mechanism of action of these cytokines on the growth of cells and their extracellular environment. 3. Alterations in TGF-beta gene expression and action in various cell types associated with the cardiovascular system may contribute to the pathophysiology of a number of diseases, such as hypertension, atherosclerosis and restenosis, as well as the development of cardiac abnormalities.
Animals↗
Vascular remodelling and molecular biology: new concepts and therapeutic possibilities.
1. Over the past decade major advances in molecular cell biology have greatly increased our understanding of the way in which many growth factor genes are expressed and regulated. This knowledge is currently being translated into investigations of the cardiovascular system. 2. Two growth factor families appear to play particularly important roles, the fibroblast growth factors and the transforming growth factors-beta. These are multifunctional growth factors capable of remodelling the vasculature through their effects on cell migration, proliferation and matrix formation. 3. An understanding of their regulation, properties and nature of their receptors is providing novel insights into the physiology and pathobiology of the vasculature. It is also providing highly specific targets for future therapy.
Animals↗