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A Bouloumié

Publications and source records attributed to A Bouloumié.

At least 19 recordsLinked to original sources
PubMed2006

Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin.

AIMS/HYPOTHESIS: Increased visceral white adipose tissue (WAT) is linked to the risk of developing diabetes. METHODS/RESULTS: We showed by fluorescence activated cell sorting analysis that human visceral WAT contains macrophages, the proportion of which increased with obesity. Selective isolation of mature adipocytes and macrophages from human visceral WAT by CD14 immunoselection revealed that macrophages expressed higher levels of chemokines (monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha, IL-8) and the adipokines resistin and visfatin than did mature adipocytes, as assessed by real-time PCR analysis. Moreover, resistin and visfatin proteins were found to be released predominantly by visceral WAT macrophages. Macrophage-derived secretory products stimulated phosphorylation of protein kinase B in human hepatocytes. CONCLUSIONS/INTERPRETATION: Resistin and visfatin might be considered to be proinflammatory markers. The increased macrophage population in obese human visceral WAT might be responsible for the enhanced production of chemokines as well as resistin and visfatin.

Abdominal Fat↗
PubMed2006

ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance.

OBJECTIVE: Inflammation in adipose tissue may link obesity to insulin resistance and atherosclerosis. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) gene is involved in the pathogenesis of atherosclerotic cardiovascular disease (CVD). We investigated ALOX5AP expression in adipose tissue, and association of gene polymorphisms with obesity and insulin resistance. DESIGN: For gene expression analysis in adipose tissue, we studied 12 lean and 36 obese women, eight lean and 13 obese men, and nine women before and 2-4 years after gastric banding surgery. For genetic analysis, we studied 231 nonobese and 350 obese men. RESULTS: The ALOX5AP protein, 5-lipoxygenase activating protein (FLAP), as well as 5-lipoxygenase (5LO) itself, were detected in adipocytes. The mRNA expression of ALOX5AP in subcutaneous adipose tissue was increased in obesity and normalized following weight reduction. High adipose tissue mRNA expression of ALOX5AP is associated with insulin resistance as measured by homeostasis model assessment (HOMA(IR)). ALOX5AP haplotypes that associate with CVD are not associated with obesity or insulin resistance. CONCLUSION: ALOX5AP is present in adipose tissue, where its expression is associated with body weight and HOMA(IR), and may provide a link between adipose tissue, inflammation and insulin resistance. Investigated ALOX5AP haplotypes are not major primary risk factors for obesity and insulin resistance.

5-Lipoxygenase-Activating Proteins↗
PubMed2004

Improvement of postnatal neovascularization by human adipose tissue-derived stem cells.

BACKGROUND: Several studies have suggested that stem cells are present in the stroma-vascular fraction (SVF) of adipose tissue (AT). METHODS AND RESULTS: To characterize the cell populations that compose the SVF of human AT originating from subcutaneous and visceral depots, fluorescence-activated cell sorter analysis was performed by use of fluorescent antibodies directed against the endothelial and stem cell markers CD31, CD34, CD133, and ABCG2. The freshly harvested SVF contained large numbers of CD34+ cells as well as cells expressing CD133 and ABCG2. Further analysis of the CD34+ cells revealed 2 CD34+ cell populations with differential expression of the endothelial cell marker CD31. Selection of the CD34+/CD31- cells by use of magnetic microbeads, followed by cell culture, demonstrated that this cell population could differentiate under appropriate conditions into endothelial cells. Moreover, in mouse ischemic hindlimb, intravenous injection of CD34(+)/CD31(-) cells was associated with an increase in the blood flow and the capillary density and an incorporation of the cells in the leg vasculature. CONCLUSIONS: Our data indicate the presence of a cell population within the SVF of human AT characterized as CD34+/CD31- exhibiting characteristics of endothelial progenitor cells. Therefore, human AT might represent a source of stem/progenitor cells useful for cell therapy to improve vasculogenesis in adults.

Adipose Tissue↗
PubMed2003

Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes.

OBJECTIVE: Adipocyte hypertrophy combined with hyperplasia, observed during the growth of adipose tissue in obesity, might promote the occurrence of hypoxic areas within the tissue. The aim of the present study is to assess the influence of hypoxia on the expression and secretion of adipocyte-derived proangiogenic factors. DESIGN AND METHODS: Differentiated 3T3-F442A adipocytes were submitted either to ambient hypoxia (5% O(2)) or to chemically induced hypoxia by treatments with cobalt chloride or desferrioxamine. The activities of the matrix metalloproteinases 2 and 9 (MMP-2 and -9) were determined by gelatin zymography. The expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor 1 alpha (HIF-1alpha), leptin, MMP-2 and -9 were studied by the use of Western blotting and RT-PCR analyses. RESULTS: Low oxygen pressure exposure and hypoxia mimics treatments were associated with increased glucose consumption and release of lactate in differentiated 3T3-F442A adipocytes. They also led to an upregulation of the expression of leptin, VEGF and MMPs. An enhanced accumulation of HIF-1alpha protein was observed in the hypoxic adipocyte nuclei. CONCLUSION: Hypoxia, in adipocytes, markedly enhances the expression of leptin, VEGF and MMPs and stimulates the HIF-1 pathway. The present data demonstrate that hypoxic adipocytes express more proangiogenic factors and suggest that hypoxia, if occurring in adipose tissue, might be a modulator of the angiogenic process.

3T3 Cells↗
PubMed2003

Culture of human adipose tissue explants leads to profound alteration of adipocyte gene expression.

Primary culture of adipose tissue has often been used to investigate pharmacological and nutritional regulation of adipocyte gene expression. Possible alteration of adipocyte gene expression by primary culture on its own has not been explored in detail. In order to address this issue, explants were prepared from human subcutaneous adipose tissue recovered from plastic surgery and maintained for 0 to 48 h in DMEM supplemented with 10 % serum. At different time points, adipocytes were isolated from the explants by collagenase digestion, and mRNA expression and lipolysis were studied. Culture was associated with an accumulation of tumor necrosis factor-alpha (TNFalpha) in the culture medium, an increase in anaerobic glycolysis, and an increase in the basal lipolysis. In parallel, a rapid and dramatic decrease in the level of mRNA encoding for several adipocyte-specific proteins such as adipocyte lipid-binding protein, hormone-sensitive lipase, lipoprotein lipase, and peroxisome proliferation activating receptor-gamma2 was observed in isolated adipocytes. These downregulations were reminiscent of a dedifferentiation process. In parallel, primary culture was associated with an increase in adipocyte beta-actin, TNFalpha, glucose transporter-1 and hypoxia-induced factor-1alpha mRNAs. Treatment of explants with agents that increase cAMP (isobutylmethylxanthine and forskolin) prevented TNFalpha production and expression and culture-induced alterations of adipocyte gene expression. These data show that primary culture of human adipose tissue explants dramatically alters adipocyte gene expression.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation.

Adipocyte hypertrophy and hyperplasia together with angiogenesis contribute to the growth of the fat mass. Because changes in the extracellular matrix (ECM) components are often associated with such cellular remodeling, we studied the adipocyte expression of the matrix metalloproteinases (MMPs) 2 and 9, two key enzymes involved in the modulation of ECM. The present study provides the first evidence that human adipose tissue produces and secretes MMP-2 and -9 as shown by gelatin zymography analysis performed on media conditioned by human subcutaneous adipose tissue and human preadipocytes in primary cultures and by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on transcripts from mature human adipocytes. The further characterization performed on the murine 3T3F442A preadipocyte cell line demonstrates that MMP expression, assessed by RT-PCR and Western blot analysis, as well as activity, assessed by gelatin zymography analysis, increased during the adipocyte differentiation, whereas the expression of tissue inhibitor metalloproteinases 1 and 2 were abolished or not affected, respectively. Finally, preadipocyte treatment with MMP inhibitors such as batimastat and captopril, as well as neutralizing antibodies, markedly decreased adipocyte differentiation as demonstrated by the inhibition in the appearance of lipogenic (triglycerides) and lipolytic (glycerol release and hormone-sensitive lipase expression) markers. These data suggest that MMP-2 and -9 could be important key regulators of adipocyte differentiation. Thus, the adipocyte-derived MMPs might represent a new target for the inhibition of adipose tissue growth.

Adipocytes↗
PubMed2000

Aging and chronic hypertension decrease expression of rat aortic soluble guanylyl cyclase.

We analyzed the influence of aging and genetic hypertension on the function and expression of soluble guanylyl cyclase (sGC) in the aortas of prehypertensive and old spontaneously hypertensive rats (SHR) as well as in age-matched normotensive Wistar-Kyoto rats (WKY). The expression of heterodimeric sGC (alpha(1) and beta(1)) was assessed at the mRNA and protein level, and its function was assessed by the relaxant responses of phenylephrine-contracted endothelium-denuded aortic rings to the nitric oxide (NO) donor sodium nitroprusside. The vasodilator potency of sodium nitroprusside was significantly reduced (P<0.05) with age (3- to 6-fold increase in the EC(50) in old WKY and SHR compared with their young counterparts) as well as with hypertension (3-fold increase in old SHR compared with age-matched WKY), whereas the vasodilator potency of sodium nitroprusside did not differ between young SHR and WKY. A similar influence of aging and hypertension on NO-stimulated GC activity was revealed at the GC expression level: Whereas the beta(1) protein content was similar in young rats of both strains, old WKY exhibited 60% lower and old SHR exhibited 80% lower beta(1) subunit protein compared with young rats (P<0.05). Moreover, the abundance of alpha(1) and beta(1) mRNA (assessed by reverse transcriptase-polymerase chain reaction) was similar in young rats but was 2.5-fold (alpha(1)) and 4.3-fold (beta(1)) lower in old SHR compared with old WKY. In conclusion, our findings show that both aging and hypertension decrease sGC expression and its NO-dependent activation in aortic tissue. Downregulation of sGC may therefore contribute to arterial dysfunction in senescence and chronic hypertension.

Aging↗
PubMed1999

Endothelial dysfunction in chronic myocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: role of enhanced vascular superoxide production.

BACKGROUND: Endothelial dysfunction of the peripheral vasculature is a well-known phenomenon in congestive heart failure that contributes to the elevated peripheral resistance; however, the underlying mechanisms have not yet been clarified. METHODS AND RESULTS: Dilator responses, the expression of protein and mRNA of the endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and soluble guanylate cyclase (sGC), and superoxide anion (O(2)(-)) and peroxynitrite production were determined in aortic rings from Wistar rats 8 weeks after myocardial infarction and compared with those in sham-operated animals. In rats with heart failure, the concentration-response curve of the endothelium-dependent vasodilator acetylcholine (after preconstriction with phenylephrine) was significantly shifted to the right, and the maximum relaxation was attenuated. Determination of expression levels of the 2 key enzymes for NO-mediated dilations, eNOS and sGC, revealed a marked upregulation of both enzymes in aortas from rats with heart failure, whereas iNOS expression was not changed. Pretreatment with exogenous superoxide dismutase partially restored the acetylcholine-induced relaxation in aortas from rats with heart failure. Aortic basal and NADH-stimulated O(2)(-) production assessed by use of lucigenin-enhanced chemiluminescence was significantly elevated in rats with chronic myocardial infarction. Peroxynitrite-mediated nitration of protein tyrosine residues was not different between the 2 groups of rats. CONCLUSIONS: These results demonstrate that endothelial dysfunction in ischemic heart failure occurs despite an enhanced vascular eNOS and sGC expression and can be attributed to an increase in vascular O(2)(-) production by an NADH-dependent oxidase. By inactivation of NO, O(2)(-) production appears to be an essential mechanism for the endothelial dysfunction observed in heart failure.

Acetylcholine↗
PubMed1999

Vascular endothelial growth factor up-regulates nitric oxide synthase expression in endothelial cells.

OBJECTIVE: Vascular endothelial growth factor (VEGF), secreted by vascular cells and a variety of tumour cells, is a potent angiogenic factor. Since nitric oxide (NO) seems to play a key role in the VEGF-induced proliferation of endothelial cells, the aim of the present study was to determine whether VEGF stimulates endothelial NO synthase (eNOS) expression and hence results in a maintained increase in NO formation. METHODS: Experiments were performed using cultured human umbilical vein endothelial cells (HUVEC) and isolated rat aortic rings. eNOS expression was assessed by Western blotting and RT-PCR analysis. RESULTS: Exposure of either confluent HUVEC or rat aortic rings to VEGF165 significantly increased eNOS mRNA and protein levels. This stimulatory effect of VEGF165 on eNOS expression was associated with an elevation in the basal production of cGMP in HUVEC, and with a leftward shift of the concentration-relaxation curve to acetylcholine in aortic rings. The VEGF-induced increase in eNOS mRNA levels was abolished by tyrosine kinase inhibitors suggesting involvement of a tyrosine kinase-dependent pathway. Since eNOS mRNA levels remained elevated in VEGF-treated cells in the presence of actinomycin D. it is likely that the VEGF-induced up-regulation of eNOS expression may be a consequence of a post-transcriptional effect on eNOS mRNA stability. CONCLUSION: The results demonstrate that VEGF enhances the expression of eNOS in native and cultured endothelial cells, an effect which may be important in the process of VEGF-induced angiogenesis.

Analysis of Variance↗
PubMed1998

Hydralazine prevents endothelial dysfunction, but not the increase in superoxide production in nitric oxide-deficient hypertension.

Dilator responses, superoxide anion-production, endothelial nitric oxide (NO) synthase and soluble guanylyl cyclase expression were determined in aortic rings from Wistar rats treated for 5 weeks either with the NO synthase inhibitor NG-nitro-L-arginine-methylester (L-NAME), L-NAME plus hydralazine or placebo. In the L-NAME-treated group, acetylcholine-induced relaxation was significantly attenuated whereas it was nearly normal in the L-NAME/hydralazine group. This difference was even more pronounced following inhibition of the endogenous superoxide dismutase using diethyldithiocarbamate. Aortic superoxide production was significantly elevated in both L-NAME-treated groups and hydralazine had no acute effect on superoxide formation. Expression of endothelial NO synthase was similar in all three groups whereas the attenuated soluble guanylyl cyclase expression in rats treated with L-NAME was nearly normalised by concomitant hydralazine treatment. These results demonstrate that in NO-deficient hypertension hydralazine treatment improves vasodilator responses but not the increased superoxide production.

Acetylcholine↗
PubMed1998

Leptin, the product of Ob gene, promotes angiogenesis.

The adipocyte-derived cytokine leptin is thought to play a key role in the control of satiety and energy expenditure. Because adipogenesis and angiogenesis are tightly correlated during the fat mass development, we tested the hypothesis that leptin is able to modulate the growth of the vasculature. Experiments were performed using cultured human umbilical venous endothelial cells (HUVECs) and porcine aortic endothelial cells. The presence of 170-kDa endothelial leptin receptor (Ob-R) was assessed in HUVECs by Western blot analysis. Reverse transcriptase-polymerase chain reaction analysis using specific oligonucleotides for the short and long Ob-R forms further revealed the expression of both Ob-R transcripts in endothelial cells. Moreover, leptin evoked a time-dependent tyrosine phosphorylation of a number of endothelial proteins, the most prominent of which were the mitogen-activated protein kinases Erk1/2. Treatment of HUVECs with leptin led to a concentration-dependent increase in cell number that was maximal at 10 ng/mL leptin and equivalent to that elicited by vascular endothelial growth factor. This effect was associated with an enhanced formation of capillary-like tubes in an in vitro angiogenesis assay and neovascularization in an in vivo model of angiogenesis. These results indicate that leptin, via activation of the endothelial Ob-R, generates a growth signal involving a tyrosine kinase-dependent intracellular pathway and promotes angiogenic processes. We speculate that this leptin-mediated stimulation of angiogenesis might represent not only a key event in the settlement of obesity but also may contribute to the modulation of growth under physiological and pathophysiological conditions in other tissues.

Adipocytes↗
PubMed1998

Vasodilator dysfunction in aged spontaneously hypertensive rats: changes in NO synthase III and soluble guanylyl cyclase expression, and in superoxide anion production.

OBJECTIVE/METHODS: Genetic hypertension is associated with an apparent endothelial dysfunction and impaired endothelium-dependent vasodilatation in response to increased flow and receptor-dependent agonists. However, the link between impaired vasodilatation and nitric oxide (NO) synthase expression is still unclear. In the present study, dilator responses were determined in the aorta and coronary circulation of 16 month old spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY). Changes in vascular reactivity were compared with alterations in superoxide anion production as well as endothelial NO synthase (NOS III) and soluble guanylyl cyclase expression. RESULTS: In the isolated perfused heart both the bradykinin- and sodium nitroprusside-induced vasodilator responses were attenuated in SHR compared to WKY. Western blot analysis revealed a parallel reduction in NOS III expression in coronary microvascular endothelial cells from SHR. Superoxide anion production in aortae from SHR was markedly elevated over that of aortae from WKY, and was almost completely abolished by pretreatment with superoxide dismutase. Superoxide dismutase induced similar relaxations in phenylephrine-preconstricted aortic rings from both SHR and WKY, but failed to restore the attenuated acetylcholine- and sodium nitroprusside-induced relaxations in SHR. No difference in NOS III expression was detected in the aortae from either strain whereas soluble guanylyl cyclase expression was markedly decreased in SHR. CONCLUSIONS: These results demonstrate that NOS III expression in different tissues is differentially affected by hypertension. Moreover, although an elevated superoxide anion production is apparent in the aorta, a reduced soluble guanylyl cyclase expression appears to account for the observed vasodilator dysfunction in SHR.

Acetylcholine↗
PubMed1997

Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production.

We investigated the effects of aortic banding-induced hypertension on the endothelium-dependent vasodilator responses in the aorta and coronary circulation of Sprague-Dawley rats. We studied the influence of hypertension on the endothelial nitric oxide synthase (NOS III) expression, assessed by Western blot and reverse transcription-polymerase chain reactions experiments, and on the superoxide anion (O2-) production. Two weeks after aortic banding, the endothelium-dependent relaxations were not altered. At this time, the expression of NOS III in the aorta and in confluent coronary microvascular endothelial cells (RCMECs) exhibited no marked changes, whereas O2- production was enhanced 1.9-fold in aortas from aortic-banded rats. Six weeks after aortic banding, the endothelium-dependent dilations were markedly impaired in the heart (50% decrease) and aorta (35% decrease). Analysis of NOS III protein and mRNA levels revealed marked increases in both aortas and confluent RCMECs (2.6- to 4-fold) from aortic-banded compared with sham-operated rats. There was no further increase in O2production in both the aorta and confluent RCMECs from aortic-banded rats. An enhanced nitrotyrosine protein level was also detected in the aorta from 6-week aortic-banded rats. These findings indicate that in hypertension induced by aortic banding, an enhanced O2- production alone is not sufficient to produce endothelial dysfunction. Endothelial vasodilator hyporesponsiveness was observed only when NOS III expression and O2- production were increased and was associated with the appearance of enhanced nitrotyrosine residues. This would suggest that the development of endothelial dysfunction is linked to an overproduction of not one, but two, endothelium-derived radicals that might lead to the formation of peroxynitrite.

Animals↗
PubMed1996

alpha2-Adrenoceptor stimulation promotes actin polymerization and focal adhesion in 3T3F442A and BFC-1beta preadipocytes.

We previously demonstrated that in white fat cell precursors alpha2-adrenoceptor stimulation lead to the phosphorylation of p44 and p42 mitogen-activated protein kinases and an increase in cell number. Regulation of cell adhesion and cell cytoskeleton plays a crucial role in the control of cell growth by various growth factors. Here, we report that in mouse 3T3F442A preadipocytes expressing 2500 fmol/mg protein of the human alpha2C10-adrenoceptor (alpha2AF2 cells), alpha2-adrenergic stimulation rapidly restored the spreading of cells previously retracted by serum withdrawal. This effect was pertussis toxin sensitive and was blocked by pretreatment of the cells with dihydrocytochalasin B (a blocker of actin polymerization), genistein (a tyrosine kinase inhibitor), or agents that increase cell cAMP content. Spreading was accompanied by cell membrane ruffling, formation of lamelipodia and filipodia, appearance of focal adhesion plaques, and induction of actin stress fibers. alpha2-Adrenergic stimulation also lead to a rapid Gi- and actin-dependent tyrosine phosphorylation of the pp125 focal adhesion kinase (FAK) as well as of the p42 and p44 mitogen-activated protein kinases. alpha2-Adrenergic-dependent spreading and FAK and mitogen-activated protein kinase phosphorylation were also observed in 3T3F442A preadipocytes permanently expressing 20 fmol/mg protein of the human alpha2C10-adrenoceptor (alpha2AF3 cells) as well as in BFC-1beta preadipocytes, which constitutively express 25 fmol/mg protein of mouse alpha2A-adrenoceptors. In BFC-1beta preadipocytes, alpha2-adrenergic-dependent spreading and pp125FAK phosphorylation were counteracted by beta-adrenergic stimulation. Our results suggest that alpha2-adrenergic control of actin polymerization and focal adhesion assembly could play a crucial role in the regulation of preadipocyte growth by the sympathetic nervous system.

Actins↗
PubMed1995

Adrenergic receptors and fat cells: differential recruitment by physiological amines and homologous regulation.

The control of fat cell lipolysis by the catecholamines involves at least four different adrenoceptor subtypes; three beta (beta 1-, beta 2-, and beta 3-ARs) and one alpha 2-adrenoceptor (alpha 2-AR). The physiological importance of the beta- and alpha 2A-ARs varies according to the species, the sex, the age, the anatomical location of fat deposits and the degree of obesity in humans and animals. The physiological amines operate through differential recruitment of these sites on the basis of their relative affinities. This point has been assessed by in vitro studies and has partly been confirmed in in vivo experiments using selected alpha/beta-AR antagonists and in situ microdialysis. The affinity of the beta 3-AR for catecholamines is less than that of the classical beta 1- and beta 2-ARs in the various species investigated. Conversely, it is the alpha 2-AR which exhibit the highest affinity for the physiological amines in all fat cells. The relative order of affinity of the various fat cell ARs for the physiological amines defined in binding studies and in vitro assays is alpha 2 > beta 1 > or = beta 2 > beta 3 for norepinephrine and alpha 2 > beta 2 > beta 1 > beta 3 for epinephrine. When considering differential beta-AR recruitment by catecholamines, it is the beta 1-AR which is always activated at the lowest norepinephrine levels, whatever the species, while the activation of the beta 3-AR requires higher norepinephrine levels. In addition to the differential recruitment, differential regulation by hormones could also occur for each fat cell AR subtype. The alpha 2-and beta 3-ARs are less prone to desensitization and down-regulation by comparison with the beta 1- and beta 2-AR.

Adipocytes↗
PubMed1994

Alpha 2-adrenergic stimulation promotes preadipocyte proliferation. Involvement of mitogen-activated protein kinases.

Primary cultures of rat preadipocytes were shown to express alpha 2- and beta-adrenoreceptors when maintained in serum-deprived medium. alpha 2-Adrenoreceptor stimulation led to an increase in cell number, whereas beta-adrenoreceptor stimulation was without effect. On 3T3-F442A clones stably transfected with the human alpha 2-C10 gene and expressing a physiologically related number of alpha 2-adrenoreceptors to overexpression, the proliferative effect of alpha 2-adrenoreceptor agonist UK14304 was proportional to the level of alpha 2-adrenoreceptor expressed in individual clones and required alpha-2 adrenoreceptor stimulation. Analysis of the signaling pathway linked to alpha 2-adrenoreceptor activation showed that the mitogenic effect was adenylyl cyclase- and protein kinase C-independent. It was pertussis toxin-sensitive, implying the involvement of pertussis toxin-sensitive G proteins. The activation of the mitogen-activated protein kinase pathway was increased after alpha 2-adrenoreceptor stimulation in both 3T3-F442 clones and rat preadipocytes and inhibited by pertussis toxin treatment. So, catecholamines are involved in the control of white preadipocyte proliferation through the alpha 2-adrenoreceptor activation, linked to the mitogen-activated protein kinase pathway.

3T3 Cells↗