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At least 145 records · Page 8Linked to original sources
PubMed1997

Redistribution of intracellular Ca2+ stores after beta-adrenergic stimulation of rat tail artery SMC.

beta-Adrenergic agonists induce the relaxation of vascular smooth muscle by a mechanism that activates the extrusion of Na+ and Ca2+ from the cell. A primary source of contractile Ca2+ resides in the sarcoplasmic reticulum (SR), which releases Ca2+ in response to vasoactive agents through inositol trisphosphate-mediated channels. To determine if smooth muscle relaxation induced by beta 2-adrenergic agonists involves the redistribution of intracellular Ca2+, we studied the effects of isoproterenol (Iso) on freshly isolated, single rat tail artery smooth muscle cells loaded with fura 2, using digital ratiometric fluorescence imaging. Stimulation with 1 microM phenylephrine (PE) or norepinephrine produced phasic and tonic increases in cytoplasmic intracellular Ca2+ concentration ([Ca2+]i) associated associated with cell shortening. Exposure to caffeine and to Ca2(+)-free solutions eliminated the phasic and tonic components, respectively, from the Ca2+ signal. Intermittent superfusion with PE or caffeine was used to evaluate SR Ca2+ stores after stimulation by Iso. Exposure to 1 microM Iso induced a time-dependent decrease in PE-activated peak and tonic [Ca2+]i without any change in resting [Ca2+]i. Intermittent stimulation with 10 mM caffeine revealed a similar decline in peak [Ca2+]i, indicating Iso-dependent depletion of SR Ca2+ stores. The Ca2+ that remained in the SR after prolonged exposure to Iso (30% of the pre-Iso level by 80 min at 22 degrees C) failed to elicit a contractile response. The cells, perfused with a Na(+)- and Ca2(+)-free medium to block Na+/ Ca2+ exchange, prevented depletion of the SR Ca2+ stores by Iso. We propose that Iso inhibits agonist-mediated Ca2+ influx through sarcolemmal Ca2+ channels and activates Ca2+ redistribution from storage sites in the SR to the extracellular compartment by a mechanism that involves Na+/Ca2+ exchange. These combined effects of Iso facilitate smooth muscle relaxation (and reduce vascular tonus) by reducing the increase in cytoplasmic Ca2+ evoked by vasoconstrictors.

Adrenergic beta-Agonists↗
PubMed1998

Attenuation of ANG II actions by adenovirus delivery of AT1 receptor antisense in neurons and SMC.

Both central and peripheral renin-angiotensin systems (RAS) are important in the development and establishment of hypertension. Thus, introducing genes relevant to RAS into neuronal and vascular smooth muscle (VSM) cells, two major targets for angiotensin (ANG) II action, is a prerequisite in considering a gene therapy approach for the control of ANG-dependent hypertension. In this study, we explored the use of adenoviral (Ad) vector to transfer AT1 receptor antisense cDNA (AT1R-AS) into neuronal and VSM cells with the anticipation of attenuation of ANG II-mediated cellular actions. Incubation of neurons and VSM cells with viral particles containing AT1R-AS (Ad-AT1R-AS) resulted in a robust expression of AT1R-AS in a majority (approximately 80%) of the cells. The expression was persistent for at least 28 days and was associated with decreases in the immunoreactive AT1 receptor protein and the maximal binding for AT1 receptor in a time- and dose-dependent manner in both cell types. ANG II stimulation of [3H]thymidine incorporation in VSM cells and norepinephrine transporter gene expression in neuronal cells were attenuated by Ad-AT1R-AS infection. Uninfected cells or cells infected with adenovirus particles containing a mutant AT1 receptor sense cDNA showed no effects on either AT1 receptor or on attenuation of ANG II's cellular affects. These observations show, for the first time, that adenovirus can be used to deliver AT1 receptor mutant sense and antisense cDNAs into two major ANG II target tissues. This consequently influences AT1 receptor-mediated cellular actions of ANG II.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1995

Differential distribution of 70-kD heat shock protein in atherosclerosis. Its potential role in arterial SMC survival.

Smooth muscle cell death may contribute to necrotic plaque rupture and subsequent thromboembolus. Stress-induced synthesis of heat-shock proteins (HSPs) normally protects cells from death, but vascular HSPs may become insufficient as cytotoxicity increases in advanced plaques. To determine whether vascular HSP content is altered near necrosis, we compared 70-kD HSP (HSP70) distribution between fibrotic and necrotic plagues in immunostained carotid endarterectomy specimens. Average levels of HSP70 immunoreactivity were compared by video densitometry between fibrotic and necrotic plaques or between their underlying media. Both necrotic plaques and their underlying media contained significantly more HSP70 staining than did fibrotic tissues. To test whether cellular HSP70 correlated with resistance to toxicity in vitro, aortic smooth muscle cells (aSMCs) were heat shocked to induce endogenous HSPs or given 2 to 50 micrograms/mL purified HSP70. Cells were then serum deprived or exposed to 12 to 96 mumol/L cholestanetriol (C3ol) or 25-hydroxycholesterol, and survival was determined. Cellular HSP70 content was assayed by immunoblotting, and protein synthesis was monitored by 35S radiolabeling. Serum deprivation inhibited general protein synthesis but induced HSP70; C3ol exposure inhibited both overall protein and HSP70 synthesis, including post-heat shock. Induction of endogenous HSPs or 10 micrograms/mL exogenous HSP70 improved viability of serum-deprived cells (P < .05 and P < .01, respectively), while only exogenous HSP70 protected against C3ol (P < .002). The results suggest that insufficient HSP70 accumulates in aSMCs residing near necrosis to protect against plaque toxicity; aSMC death might then occur, allowing resident macrophages to degrade and destabilize the matrix, leading to rupture.

Animals↗
PubMed1997

Induction of vascular SMC proliferation by urokinase indicates a novel mechanism of action in vasoproliferative disorders.

The urokinase-type plasminogen activator (UPA) and its receptor are expressed in the vasculature and are involved in cell migration and remodeling of the extracellular matrix in the neointima. Vessels with atherosclerosis or neointimal hyperplasia, when compared with normal vessels, contain high UPA activity as well as increased levels of UPA receptor. In this study, we have identified the stimulation of vascular smooth muscle cell proliferation as a novel activity for UPA in the vessel wall. High-molecular-weight-UPA (12-200 nmol/L range) stimulated DNA synthesis and cell proliferation, which was half that induced by fetal calf serum or by platelet-derived growth factor-BB. UPA did not induce growth of endothelial cells, and tissue-type plasminogen activator showed no activity on either cell type. Induction of proliferation required the complete UPA molecule but was independent of the proteolytic activity of UPA, whereas neither the amino-terminal fragment nor the catalytic domain by itself was mitogenic. UPA also stimulated c-fos/c-myc mRNA expression and mitogen-activated protein kinase activity in smooth muscle cells. Blocking monoclonal antibodies against the UPA receptor and the enzymatic removal of receptors were ineffective in inhibiting the mitogenic effect of UPA, suggesting a UPA receptor-independent mechanism. Thus, we provide evidence for a novel function of UPA on vascular smooth muscle cell proliferation that, together with its previously documented involvement in regulating pericellular proteolysis-related events and cell migration, provides additional evidence for a role in the pathogenesis of atherosclerosis/restenosis.

Aorta↗
PubMed2007

Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice.

Interleukin 4 receptor alpha (IL-4Ralpha) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response-driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Ralpha pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Ralpha-deficient mice (SM-MHC(Cre)IL-4Ralpha(-/lox)) were generated and characterized to uncover any role for IL-4/IL-13 in this non-immune cell type in response to Nippostrongylus brasiliensis infection. IL-4Ralpha was absent from alpha-actin-positive smooth muscle cells, while other cell types showed normal IL-4Ralpha expression, thus demonstrating efficient cell-type-specific deletion of the IL-4Ralpha gene. N. brasiliensis-infected SM-MHC(Cre)IL-4Ralpha(-/lox) mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Ralpha-responsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions.

Animals↗
PubMed1988

[Studies on the roles of insulin-like growth factor-1 (IGF-1)/somatomedin C (SMC) during pregnancy].

Studies in human as well as animal experiments have proved that IGF-1/SMC, which shows mitogenic activities in a wide variety of cell types, stimulates growth in vitro and in vivo. The aim of this study was to investigate the roles of IGF-1/SMC on fetal growth during pregnancy by measuring IGF-1/SMC, insulin, C-peptide, human placental lactogen (hPL), and GH and PRL concentrations in maternal and fetal plasma, and by clarifying the changes of IGF receptor in human fetal liver microsomal membranes during pregnancy. Maternal plasma IGF-1/SMC concentrations were not distinguishable from those of nonpregnant women (9.2 +/- 1.7 nmol/l) in the 1st and 2nd trimester of gestation; however, they showed a gradual increase after the 30th week of gestation, reaching 12.7 +/- 5.4 at term. They possessed a significant positive correlation with hPL (r = 0.45, p less than 0.05) and PRL (r = 0.38, p less than 0.05) but not with GH (r = 0.39, NS). On the other hand, IGF-1/SMC in cord plasma could be first detected in the 30th week of gestation, and it increased gradually until term but had no significant correlation with that in maternal plasma. Furthermore, it possessed an intimate correlation with C-peptide (r = 0.30, p less than 0.05) but not with GH or PRL. Additionally, IGF-1/SMC in cord plasma had a positive correlation with birth weight (r = 0.60, p less than 0.005). On the other hand, specific binding of 125I-IGF-1 and -II to liver microsomal membranes which was also displaced by nonlabeled insulin could be detected in human fetuses at various gestational ages. Scatchard analyses indicated that the binding affinity, which was 0.14 +/- 0.05(x 10(9)M-1) in the fetal liver before the 19th week of gestation, increased after the 19th week of gestation (0.58 +/- 0.12); conversely, the binding capacity was lower after the 19th week of gestation (0.15 +/- 0.08 x 10(-12) moles/mg protein) compared with that before the 19th week (0.51 +/- 0.25). These results suggest that (1) plasma IGF-1/SMC might be produced in fetal sites and its regulating mechanism is different from that in maternal sites, and that (2) IGFs might play an important role in human fetal growth and development by its affect via IGF or insulin receptors on the human fetal liver.

C-Peptide↗
PubMed1989

[A case of leprechaunism with disorders of insulin-like growth factor-I(IGF-I)/somatomedin C(SMC) binding protein and its receptor].

Leprechaunism is a rare genetic disorder characterized by physical abnormalities, intrauterine and postnatal growth retardation, poorly developed subcutaneous fat and muscle at birth, and early death. This patient, who was a 1.5 year-old female with typical clinical features of leprechaunism, had relatively high levels of plasma GH and IGF-I/SMC but no glucose intolerance or insulin resistance. Studies were undertaken to elucidate (1) the differences among some kinds of methods for IGF-I/SMC measurement, (2) the distribution patterns of IGF-I/SMC between two kinds of its binding protein (SMBP) in plasma, and (3) the dynamics of IGF-I/SMC receptor in her erythrocytes and liver microsomal membranes. The results were as follows: (1) The level of IGF-I/SMC measured by Nichols radioimmunoassay kit was 1.33U/ml, which was higher than that of infants the same age. Conversely, it was lower than that of the control which was measured by radioimmunoassay using recombinant IGF-I/SMC after acid-ethanol or Seppak C18 extraction. (2) By Sephadex G150 gel-chromatography, immunoreactive IGF-I/SMC was eluted predominantly in 150K region, and two apparent peaks of unsaturated somatomedin binding protein (USBP) were determined in a neonatal infant (appropriate to date), a normal adult and an infant of the same age as this patient. On the other hand, immunoreactive IGF-I/SMC was located only in the fractions corresponding to 40K region, and only one peak of USBP could be estimated in the region of 40K dalton. (3) The IGF-I/SMC receptor in the patient's erythrocytes possessed significantly lower binding affinity but higher binding capacity in comparison with that of the normal neonate and adult. In addition, the receptor in liver microsomal membranes obtained from this patient at autopsy also indicated lower affinity but higher capacity than that of fetuses at more than 19 weeks of gestation. This was coincident to that of fetuses less than 19 weeks of gestation. These results suggested that this patient resembled the intrauterine fetus before midgestation not only in the co-relationship among GH, IGF-I/SMC and its binding proteins, but also in the characteristics of its receptor. The severe growth retardation existing in this patient may be, at least partly, due to the abnormality and/or immaturity of IGF-I/SMC function. It is speculated that leprechaunism could be classified in relation to fetal growth mechanism by aspects of biological functions of IGF-I/SMC during development.

Abnormalities, Multiple↗
PubMed1989

[Circulating forms of insulin-like growth factor-I(IGF-I)/somatomedin C (SMC) in fetal life: relationship between changes in its binding proteins and growth delay during intrauterine and post-natal periods].

IGF-I/SMC shows mitogenic activities in a wide variety of cell types and stimulates cell growth in vitro and in vivo. Unlike most other peptide hormones, IGF-I/SMC circulates in the plasma as macromolecular complexes with specific plasma binding proteins, approximate molecular weight of 150K and 40K daltons. In order to elucidate the roles of IGF-I/SMC for fetal and postnatal development, the levels of plasma IGF-I/SMC, distribution of circulating IGF-I/SMC on its binding proteins, and profiles of unsaturated somatomedin binding proteins (USBP) were estimated in newborns and a growth-retarded infant (leprechaunism). The concentrations of IGF-I/SMC in cord plasma increased gradually after the 28th week of gestation and reached 37.3 +/- 14.6 ng/ml (Mean +/- S.D.) in full term infants. Although the levels of IGF-I/SMC in cord plasma were significantly lower than those in non-pregnant women (188 +/- 58), they showed a positive correlation with birth weight and relative birth weight (R.B.W.: percentage comparison to the average birth weight of normal infants in the same gestational week). In adult plasma, immunoreactive IGF-I/SMC was eluted predominantly in 150K dalton region (73.5%) and to a lesser extent (26.5%) in 40K dalton, and two apparent peaks of USBP could also be determined in both 150K and 40K dalton regions. On the other hand, in fetal plasma 84.4% of immunoreactive IGF-I/SMC was eluted in 40K region on the 20th week, but on the 26th week, 71.6% of IGF-I/SMC was eluted in 150K region and after the 35th week, more than 70% of IGF-I/SMC was determined in 150K region as observed in adult plasma. However, 150K.USBP could not be detected in cord plasma obtained from appropriate-for-date(AFD) infants until after the 35th week of gestation. Additionally, a positive correlation was demonstrated between 150K.USBP/40K.USBP ratio and birth weight. Some cases of small-for-date(SFD) infants whose IGF-I/SMC circulated mainly as 150K complex could catch up on their growth early in postnatal life. However, in the SFD newborns, if either 150K.USBP or 150Kcomplex of IGF-I/SMC could not be detected, their growth spurt was remarkably delayed until a year after birth. Furthermore, the similar disorders of IGF-I/SMC distribution and its USBP profile were also observed in the case of leprechaunism, who showed severe intrauterine and postnatal growth retardation.(ABSTRACT TRUNCATED AT 400 WORDS)

Birth Weight↗