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PubMed2000

Epidermal growth factor is decreased in liver of rats with biliary cirrhosis but does not act as paracrine growth factor immediately after hepatectomy.

BACKGROUND/AIMS: Epidermal growth factor, a potent mitogen for hepatocytes and cholangiocytes, is thought to act as an immediate-early gene after partial hepatectomy. Since regeneration is impaired in cirrhosis, we explored the expression of epidermal growth factor in cirrhotic rat liver immediately after partial hepatectomy. METHODS: Cirrhosis was induced by bile duct ligation (n=21); sham-operated animals served as controls (n=21). Twenty-five days after initial surgery animals were subjected to 70% partial hepatectomy or sham operation; the liver was sampled before surgery and 20, 40 and 90 min thereafter. Epidermal growth factor mRNA levels were assessed by quantitative reverse transcription polymerase chain reaction. Protein expression was estimated by immunohistochemistry using a polyclonal antibody against epidermal growth factor. RESULTS: Before hepatectomy, epidermal growth factor mRNA averaged 70.3+/-39.9 pg/microg of total RNA in controls; this was markedly decreased to 21.9+/-12.7 pg/microg RNA in bile duct ligation (p<0.01). Epidermal growth factor mRNA did not increase after partial hepatectomy in either group, with the exception of sham-operated controls. Immunohistochemistry revealed that partial hepatectomy had no effect on epidermal growth factor expression. Hepatocytes showed uniformly cytosolic epidermal growth factor in controls, while in bile duct ligation immunostaining was faint or absent. Cholangiocytes exhibited a strong cytosolic staining in all experimental groups. CONCLUSIONS: The present study shows that epidermal growth factor is reduced in the cirrhotic liver. This could contribute to the loss of parenchymal liver tissue observed in cirrhosis. The lack of up-regulation after PH sheds doubt on the role of epidermal growth factor as an immediate-early gene in hepatic regeneration. Further, we demonstrate that epidermal growth factor accumulates in cholangiocytes. This observation is strong evidence for involvement of the mitogen epidermal growth factor in the proliferation of bile ducts during cirrhogenesis.

Animals↗
PubMed1998

Expression of different isoforms of TGF-beta and the latent TGF-beta binding protein (LTBP) by rat Kupffer cells.

BACKGROUND/AIMS: Kupffer cells (liver resident macrophages) make an important contribution to the perpetuation of liver diseases by synthesis and secretion of TGF-beta. In some cell types TGF-beta, is expressed as a large latent complex containing the latent TGF-beta binding protein (LTBP) in addition to the N-terminal TGF-beta precursor (latency associated peptide). This study aimed to identify LTBP expression in rat Kupffer cells. METHODS: Cells were isolated from rat liver by collagenase-pronase reperfusion, purified and cultured under standard conditions. TGF-beta and LTBP expression were characterized using alkaline phosphatase-anti-alkaline phosphatase immunostainings, reverse transcription-polymerase chain reaction and immunoprecipitation of metabolically labeled proteins. RESULTS: Immunostainings of Kupffer cells with anti-sera against LTBP-1 (ab 39) and LTBP-2 indicated the expression of both LTBP isoforms in addition to the expression of latency associated peptide and TGF-beta. Transcripts of three LTBP isoforms (LTBP-1,-2,-3) and TGF-beta isoforms (TGF-beta-1,-2,-3) were detectable by reverse transcription-polymerase chain reaction. The LTBP-1D splice variant missing a part of the proteinase sensitive hinge region which has recently been described in hepatic stellate cells is expressed in Kupffer cells, too. Metabolic labeling of Kupffer cells with [35S]-Met/Cys followed by immunoprecipitation of the conditioned media using antisera against LTBP-1 and LTBP-2 indicated the secretion of high molecular mass TGF-beta complexes containing LTBP proteins of 230 and 170 kDa (LTBP-1) or 230 kDa (LTBP-2). CONCLUSION: The results show that Kupffer cells partly synthesize and release TGF-beta as large latent complexes. This requires the extracellular activation of TGF-beta as a prerequisite for receptor binding and cellular signaling.

Animals↗
PubMed1999

Paracrine or virus-mediated induction of decorin expression by endothelial cells contributes to tube formation and prevention of apoptosis in collagen lattices.

Resting endothelial cells express the small proteoglycan biglycan, whereas sprouting endothelial cells also synthesize decorin, a related proteoglycan. Here we show that decorin is expressed in endothelial cells in human granulomatous tissue. For in vitro investigations, the human endothelium-derived cell line, EA.hy 926, was cultured for 6 or more days in the presence of 1% fetal calf serum on top of or within floating collagen lattices which were also populated by a small number of rat fibroblasts. Endothelial cells aligned in cord-like structures and developed cavities that were surrounded by human decorin. About 14% and 20% of endothelial cells became apoptotic after 6 and 12 days of co-culture, respectively. In the absence of fibroblasts, however, the extent of apoptosis was about 60% after 12 days, and cord-like structures were not formed nor could decorin production be induced. This was also the case when lattices populated by EA.hy 926 cells were maintained under one of the following conditions: 1) 10% fetal calf serum; 2) fibroblast-conditioned media; 3) exogenous decorin; or 4) treatment with individual growth factors known to be involved in angiogenesis. The mechanism(s) by which fibroblasts induce an angiogenic phenotype in EA.hy 926 cells is (are) not known, but a causal relationship between decorin expression and endothelial cell phenotype was suggested by transducing human decorin cDNA into EA.hy 926 cells using a replication-deficient adenovirus. When the transduced cells were cultured in collagen lattices, there was no requirement of fibroblasts for the formation of capillary-like structures and apoptosis was reduced. Thus, decorin expression seems to be of special importance for the survival of EA.hy 926 cells as well as for cord and tube formation in this angiogenesis model.

Adenoviridae↗
PubMedDate not supplied

Neuroendocrine vs. paracrine control of follicle-stimulating hormone.

In spite of the pivotal role FSH plays in the regulation of gametogenesis, we are far from understanding the regulatory mechanisms involved in the control of its synthesis, secretion, and functions. Part of the problem relates to its molecular heterogeneity and the unavailability of assay methods capable of distinguishing the various isoforms of FSH. Recent work has confirmed the existence of two modes of FSH secretion, the basal and the episodic modes. The major portion of FSH secretion appears to be in the basal mode. The episodic mode appears to consist of both GnRH-associated and non-GnRH-associated pulses of FSH. The intracellular mechanisms by which differential release of LH and FSH are facilitated by GnRH are just beginning to be unraveled and may involve different second-messenger systems. Local pituitary regulators such as activins, inhibins, and follistatins are receiving considerable attention in recent years as a means by which differential release of LH and FSH can be facilitated by GnRH and other neuroendocrine factors. In parallel, the search for a selective FSH-releasing factor (FSH-RF) continues. Identification of variant forms of GnRH in recent years has opened up the possibility that one GnRH variant may be the long-sought-after FSH-RF. From a functional aspect, an understanding of how FSH heterogeneity is regulated is also important, as the different mixes of FSH isoforms have the ability to fine-tune the follicular recruitment and selection process. This review focuses on the recent advances made in the neuroendocrine and paracrine regulation of FSH synthesis/secretion/heterogeneity and pinpoints areas of gaps in our knowledge.

Activins↗
PubMedDate not supplied

Progress toward understanding follicle development in vitro: appearances are not deceiving.

The interactive factors that influence the developmental progress of a follicle and determine whether it will progress to ovulation or toward atresia, are highly complex. In vitro models are being developed that are intended to provide a simplified environment to facilitate understanding of the dynamics of the processes involved. The purpose of this overview is to evaluate progress to date and to focus attention on issues that need more careful consideration to improve the usefulness of the models. Basically, two approaches exist. One, attached follicle culture, employs either enzyme-digested or mechanically harvested follicles depending on the method but allows attachment of the follicles to the culture surface. This produces a rounded or flattened structure (depending on culture conditions) that is no longer an intact follicle. During this culture, the cells reorganize themselves, some remaining in contact with the oocyte and others attaching to the culture surface and proliferating. The other approach, intact 3-dimensional follicle culture, employs mechanically dissected preantral follicles that are cultured as free-floating intact structures. Intact follicle culture emulates the in vivo developmental pattern of the follicle more closely than a non-intact structure can, and thereby provides a favorable model to investigate the interaction between hormonal and paracrine factors in the development of the follicle in isolation from systemic effects. For example, intact follicle culture has begun to be used to investigate the local effects of several different steroids. In addition, the local effects of inhibin, activin, and follistatin and their interactions with locally produced growth factors and steroids as well as synergy with gonadotrophins are beginning to be investigated. In our laboratory, the focus is on the roles of gonadotrophins at different stages of follicle development, particularly the effect of FSH isoforms in modulating follicle development in vitro. Finally, an important issue that urgently needs to be addressed, for future studies of in vitro follicle development, is the rationalization and standardization of follicle culture conditions.

Activins↗
PubMed1997

Paracrine effect of seminiferous tubule factors on rat Leydig cell testosterone production: role of cytoskeleton.

In Percoll purified Leydig cells from mature rat we have demonstrated that the basal testosterone production (9.5 ng/10(6) Leydig cells/24 h) is increased 10-fold in presence of a saturating amount of hCG (1 IU/mL) and diminished in a dose-related manner when larger concentrations of gonadotropin are used to reach 14 ng/10(6) Leydig cells for 50 IU of hCG. If 40% (v/v) seminiferous tubule medium (STM) is added together with hCG (1 IU/mL) to the incubation medium, a further increase (62%) of testosterone output is noticed. Obviously, when the testosterone production is low as a consequence of a higher dose of hCG (50 IU/mL), the STM (80%) improves the steroid synthesis five-fold (67.4 ng). Concerning the cytoskeletal components (microtubules, intermediate filaments and microfilaments) which have been examined in presence or absence of hCG and STM, we have found a rearrangement of cytoskeletal elements as well as cell-shape changes in relation with hormonal activity of the cells. The most prominent alterations of cytoskeletal elements have been observed after 24 h of incubation with 1 IU/mL of hCG added together with 80% of STM. The obtained results suggest that paracrine factor(s) presents in STM and acting in synergy with LH/hCG generate(s) the rearrangement of cytoskeletal structures which, in turn, facilitates the availability of cholesterol for the mitochondria and finally enhances the testosterone production in the rat Leydig cells.

Animals↗
PubMed2001

[Developmental genes and heart disease].

The past three years can be considered in cardiology as critical for understanding the relevance of developmental genes in the adult cardiac physiology. Also, for the first time, endogenous control of programmed cell death has been demonstrated to mark the transition between normal adaptation and cardiac hypertrophy. Most of this work has been based on previous analysis using molecular markers of cardiac determination and differentiation, work that has served a double aim: First, the determination of the cellular process that contribute to the specification of the working heart and secondly, the characterization of key regulatory factors in cardiogenesis. These studies in conjunction with the recent availability of single gene mutation in transgenic mice have furnished a new perspective in the nature of cardiac defects either in shape or function. Here we review some of the key factors in cardiac morphogenesis from the perspective of the analysis of gene mutation.

Genes↗
PubMed2001

Gonadotropic control of ovarian follicular growth and development.

Development-related paracrine cues that sensitize follicles to follicle stimulating hormone (FSH) and luteinizing hormone (LH) are crucial to the emergence of a single dominant follicle in each ovulatory menstrual cycle. Sex steroids, insulin-like growth factors and members of the transforming growth factor-beta superfamily are key players in the follicular paracrine system. FSH acts through membrane-associated granulosa cell receptors (FSHR) to stimulate granulosa cell proliferation and differentiation. The most responsive follicle at the beginning of the cycle is the first to produce estrogen and express granulosa cell LHR. Paracrine signalling activated by FSH and LH sustains growth and oestrogen secretion until an ovulation-inducing LH surge is discharged by the pituitary gland. LH then reprograms granulosa cell function, leading to terminal differentiation (luteinization) rupture of the follicle wall, and release of the fertilizable egg. The genes regulated by the LH surge orchestrate profound changes in sex steroid production, metabolism and action which are necessary for ovulation. Preovulatory granulosa cells also increase their ability to metabolise cortisone to cortisol, which may be part of a local anti-inflammatory mechanism to promote rapid healing of the ruptured ovarian surface.

Animals↗
PubMed2001

Transforming growth factor-alpha stimulates proliferation of rat Sertoli cells.

The number of Sertoli cells is positively correlated with the number of germ cells produced in the testis, but the regulation of Sertoli cell proliferation and final density is poorly understood. Using non-aggregated Sertoli cells from 8 to 9-day-old rat testes, highly enriched by lectin binding, we explored effects of Sertoli cell growth factor candidates in vitro. Proliferation was assessed by 3H-thymidine incorporation, bromodeoxyuridine labeling and supravital staining, and FSH was used as positive control. Transforming growth factor-alpha (TGF-alpha) was found to stimulate Sertoli cell proliferation in a dose-dependent manner. Epidermal growth factor (EGF) and betacellulin mimicked the effect, demonstrating specificity of the response as they share receptors with TGF-alpha. Insulin-like growth factor I and II, acidic and basic fibroblast growth factor and stem cell factor lacked significant stimulatory effects. We conclude that EGF/TGF-alpha is a growth factor for Sertoli cells in vitro, possibly contributing to paracrine regulation of Sertoli cell proliferation in vivo.

Animals↗
PubMed2001

Paracrine action of keratinocyte growth factor (KGF) during ruminant mammogenesis.

Keratinocyte growth factor (KGF) is a stroma-derived mitogen mediating epithelial-stromal interactions. We investigated the role of KGF during epithelial-stromal interactions accompanying ruminant mammogenesis. Target-specificity of KGF was demonstrated in that KGF-stimulated proliferation of bovine mammary epithelial, but not ovine mammary stromal cells. Consistent with a paracrine function, 4.6, 2.4, 1.5 and 0.9 kb mRNA transcripts were expressed by bovine stromal, but not epithelial cells. Within the ovine mammary gland, 2.4 and 1.5 kb KGF mRNAs were expressed in the fat pad while only the 2.4 kb transcript was transcribed in parenchyma. The abundance of KGF mRNA was greater in the extra-parenchymal fat pad than in the contralateral epithelium-free fat pad prior to puberty, and was less in parenchyma than in the intact or epithelium-free fat pads. Ovariectomy tended to increase KGF transcription while estrogen reduced expression. Of several tissues, mammary parenchyma expressed a 2.4 kb mRNA while adipose tissues expressed a 1.5 kb transcript. These results demonstrate local and systemic regulation of KGF transcription and support a paracrine role for KGF during ruminant mammogenesis.

Animals↗
PubMed2002

The initiation of follicle growth: the oocyte or the somatic cells?

The initiation of follicle growth is defined as the transition of primordial follicles from the quiescent to the growth phase. We have shown that follicle growth initiation consists of two distinct, consecutive phases. The first phase is characterized by the transformation of granulosa cells from flattened to cuboidal in shape and by their proliferation, this coincides with follistatin expression. During the second phase, an increase in the number of granulosa cells is accompanied by an increase in the size of the oocyte. Evidence from other species confirms this observation. It seems that a prerequisite for initiation of oocyte growth is the presence of cuboidal granulosa cells. The vast majority of bovine primordial follicles enter the first phase of growth when cultured in serum-free medium. Similar results have been obtained for human primordial follicles. Two proteins of oocyte origin, GDF9 and BMP15, play an essential role in granulosa cell proliferation beyond the primary stage. It can be speculated that the regulation of follicle growth initiation is a two-phase event: the first phase depends on locally produced inhibitory and stimulatory factor(s); in the second phase the follicle become an autonomous unit, whose further development depends on oocyte-produced GDF9/BMP15 and the kit ligand derived from granulosa cells.

Animals↗
PubMed2002

Connective tissue growth factor in the ovarian paracrine system.

The endocrine actions of follicle stimulating hormone and luteinising hormone on ovarian cells are transduced by locally produced paracrine factors that regulate the formation of extracellular matrix, proteolytic enzymes and protease inhibitors, which continuously remodel the parenchymal environment in which follicles develop. We recently identified connective tissue growth factor (CTGF) as a gene expressed during the predifferentiated stage of granulosa cell development in rat ovary. The CTGF gene encodes a protein that is implicated in the regulation of connective tissue synthesis, mototaxis, angiogenesis and cellular interaction with ECM at various sites in the body. Stimulation of granulosa cells by FSH in vitro and in vivo induces follicular maturation associated with down-regulation of granulosa cell CTGF mRNA expression. The gene remains expressed in cells of the innermost (antrally located) granulosa compartment up to and after the point of ovulation. Based on the inferred biological properties of CTGF protein and the spatiotemporal pattern of CTGF mRNA expression in the ovary, we postulate roles for ovarian CTGF during early stages of follicular development and after ovulation in the formation of the corpus luteum.

Animals↗
PubMed1997

Identification of neuropeptides in the midgut of parasitized insects: FLRFamides as candidate paracrines.

Parasitism of Manduca sexta (Lepidoptera: Sphingidae) larvae by the braconid wasp Cotesia congregata (Hymenoptera: Braconidae) leads to accumulation of peptides in host neurons and neurosecretory cells of the central nervous system (CNS) and neurons and endocrine/paracrine cells of the midgut. This accumulation has now facilitated the characterization of two new members of the FLRFamide family from midguts of parasitized larvae. The peptides, given the names F24 and F39, are 24 and 39 amino acids in length with the sequences VRDYPQLLDSGMKRQDVVHSFLRFamide and YAEAAGEQVPEYQALVRDYPQLLDSGMKRQDVVHSFLRFamide. The sequence of F24 is identical to the C-terminal 24 amino acids of F39. The C-terminal 10-mer of each is identical to a previously characterized decapeptide neurohormone (F10). This sequence is preceded by a potential processing site. In nonparasitized insects F39 was present at several-fold the amount of F24. In parasitized insects F24 and F39 accumulate in the middle and posterior regions of the midgut, which are enriched in endocrine/paracrine cells reacting with FLRFamide antisera. In the combined brain and subesophageal ganglion F39 was not detected and the amount of F24 never exceeded 2 fmol per Br/SEG. Of the three peptides, only F10 was found in the hemolymph. Thus, F24 and F39 may be intermediates in the biosynthesis of F10 and may themselves be released locally from endocrine/paracrine cells in the midgut epithelium.

Amino Acid Sequence↗
PubMed1999

Targeted ablation of gonadotrophs in transgenic mice affects embryonic development of lactotrophs.

Ablation of pituitary gonadotrophs was obtained in transgenic mice expressing diphtheria toxin A (DTA) under control of the -313/+48 bovine glycoprotein hormone alpha-subunit (alphaSU) promoter, previously shown to be active in mouse gonadotrophs but not in thyrotrophs. Development of hormone-producing cell types was assessed on the day of birth by computer-assisted image analysis on paraffin-embedded, immunostained pituitary sections. Six out of 50 transgenic F0 ('founder') mice (3 males and 3 females) showed a nearly complete disappearance of gonadotrophs but not of thyrotrophs. The number of lactotrophs and the relative area occupied by PRL-immunoreactivity were significantly reduced in the gonadotroph-depleted mice. The size of lactotroph clusters was smaller in the absence of gonadotrophs. The number and immunoreactive area of corticotrophs and somatotrophs, on the other hand, were not significantly affected by gonadotroph ablation. Based on the reported evidence that fetal ovaries do not produce steroid hormones as a result of lack of expression of at least three of the steroidogenic enzymes, P450scc, P450c17, and P450arom, the present observations can hardly be explained by a decline in estrogen levels due to gonadotroph ablation. Rather, the present data indicate that gonadotrophs directly stimulate the development of lactotrophs during fetal and early postnatal life, consistent with previous in vitro observations, and/or that gonadotrophs may share a cell-lineage relationship with a subpopulation of lactotrophs.

Animals↗
PubMed1999

Hormone regulation of chondrocyte differentiation and endochondral bone formation.

Endochondral bone formation, the formation of calcified bone on a cartilage scaffold, occurs during skeletal development, post natal growth and during bone remodelling and fracture repair. The epiphyseal growth plates represent classical tissues in which to study the ossification process, which requires two co-ordinated components; progressive chondrocyte differentiation and cartilage neovascularisation. Many gene knockout studies have produced new insights regarding how chondrocyte differentiation and angiogenesis are controlled at the molecular level. Additional genetic studies have produced new information regarding the role of hormones in the regulation of endochondral bone formation. The new challenge for the future is to determine how bone formation and turnover is physiologically regulated and co-ordinated to ensure that skeletal development and growth progresses correctly. This study reviews the emerging data in this quickly growing field which should ultimately provide fundamental insights into the normal control of endochondral ossification.

Animals↗
PubMed2000

Growth and paracrine factors regulating follicular formation and cellular function.

The purpose of this paper is to review, using fetal sheep as the animal model, aspects of ovarian development related to follicular formation and to report on the identity of growth and paracrine factors which might be involved in this process. Before follicular formation there is a massive and sustained colonisation of the fetal ovary by mesonephric cells, which become a precursor source of follicular cells. From within the ovarian medulla, somatic 'cell-streams' branch into the cortex around nests of oogonia and oocytes. These 'cell-streams', which contain elongated cells with either flattened or cuboidal shaped nuclei, express steroidogenic factor-1 (SF-1), steroid acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), cytochrome P450(scc), and P450(aromatase) mRNA and/or protein. Follicles form from the association of an oocyte with the 'cell-stream' with either a single layer of flattened cells (i.e. type 1 follicle) or with a mixture of flattened and cuboidal cells (i.e. type 1a follicle). These newly-formed follicles have between 3 and 57 somatic cells (i.e. granulosa cells) and contain oocytes which vary in diameter between 23 and 52 microm. Newly formed and early growing follicles have been identified with growth factors or growth factor receptors in either the oocytes or granulosa cells. Many of the growth factors are from the TGFbeta superfamily and are expressed in a cell- and stage-specific manner.

Animals↗
PubMed1998

Paracrine production of nerve growth factor during rat dorsal root ganglion development.

Nerve growth factor is a target derived growth factor. In the peripheral nervous system, it is produced by tissues innervated by the sympathetic nervous system and small sensory neurons. In the present study, we tested the hypothesis that an alternate source of nerve growth factor must be available to support dorsal root ganglion neurons before they make connection with the target. Using reverse transcriptase polymerase chain reaction (RT-PCR), we detected nerve growth factor mRNA at embryonic day 12 to 17, but not in adult dorsal root ganglia. In situ hybridization studies revealed positive staining in satellite/supportive cells juxtaposed to dorsal root ganglion neurons. Our study suggests that nerve growth factor from supporting cells may have a paracrine function during development of primary sensory neurons.

Animals↗
PubMed2001

Interaction between paracrine tumor necrosis factor-alpha and paracrine angiotensin II during myocardial ischemia.

OBJECTIVES: The purpose of this study was to explore interactions between paracrine angiotensin II (Ang-II) and tumor necrosis factor-alpha (TNF-alpha) during myocardial ischemia. BACKGROUND: Ischemic myocardium releases significant amounts of TNF-alpha. This paracrine release correlated with postischemic myocardial injury. Other studies showed myocardial protection obtained by the use of angiotensin-converting enzyme inhibitors (i.e., captopril) and the Ang-II type 1 receptor antagonist losartan after ischemia. The possibility that these agents decrease TNF-alpha synthesis has not yet been investigated. METHODS: Using the modified Langendorff model, isolated rat hearts underwent either 90 min of nonischemic perfusion (control group) or 1 h of global cardioplegic ischemia. In both groups, either captopril (360 micromol/liter) or losartan (182.2 micromol/liter) was added before ischemia. The hearts were assayed for messenger ribonucleic acid (mRNA) expression and effluent TNF-alpha levels. In addition, cardiac myocytes were incubated in cell culture with Ang-II. RESULTS: After ischemia, TNF-alpha mRNA expression intensified from 0.63 +/- 0.06 (control group) to 0.92 +/- 0.12 (p < 0.03), and effluent TNF-alpha levels were 711 +/- 154 pg/ml. The TNF-alpha mRNA expression declined to 0.46 +/- 0.07 (p < 0.01) and 0.65 +/- 0.08 (p < 0.02) in captopril- and losartan-treated hearts, respectively. Effluent TNF-alpha was below detectable levels. Concentrations of TNF-alpha in supernatants of incubated cardiac myocytes treated with 10 and 50 nmol/liter of Ang-II were 206.0 +/- 47.0 pg/ml and 810 +/- 130 pg/ml, respectively (p < 0.004). When pretreated with 700 micromol/liter of losartan, TNF-alpha was below detectable levels. CONCLUSIONS: This study presents an original explanation for previously reported myocardial protection after ischemia, obtained by the use of captopril and losartan. These drugs reduce TNF-alpha synthesis, providing strong evidence of active interactions between paracrine TNF-alpha and Ang-II in the evolution of the ischemic cascade.

Angiotensin II↗