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PubMed1993

Endothelial cells exhibiting angiogenesis in vitro proliferate in response to TGF-beta 1.

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in the positive regulation of angiogenesis in vivo, whereas it inhibits the proliferation of endothelial cells in vitro. To reconcile these apparently contradictory effects, we have investigated the effect of TGF-beta 1 on bovine aortic endothelial cells that exhibit spontaneous angiogenesis in vitro. We show that concentrations of TGF-beta 1 which stimulate proliferation of cells that form endothelial cords and/or tubes inhibit proliferation of the same cells grown at subconfluent densities. An increase in cell number of 35% over control cultures was achieved with 0.5 ng TGF-beta 1/ml. The proliferative effect was blocked by antibodies against TGF-beta. Immunological detection of BrdU-labeled nuclei revealed an increase greater than 220% in cells treated with TGF-beta 1. Moreover, a population of cells within the cords appeared to be a selective target for this cytokine. The stimulatory effect was not restricted to bovine aortic endothelial cells, as similar results were obtained with endothelial cells derived from rat microvessels. Significant levels of active TGF-beta 1 were detected in cultures containing cords/tubes, whereas only latent TGF-beta 1 was detected in subconfluent cultures. We show further that endothelial cells exhibiting angiogenesis in vitro secrete plasminogen activator, an enzyme that regulates activation of TGF-beta. The major increases in mRNA transcripts for extracellular matrix proteins that are typically associated with TGF-beta 1 were not seen in cells exhibiting angiogenesis in vitro. Since the formation of tubular networks requires both invasion and proliferation, we propose that TGF-beta 1 is a major morphoregulatory factor in angiogenesis that specifically controls endothelial cell proliferation and extracellular matrix turnover.

Animals↗
PubMed1993

Fibronectin promotes the elongation of microvessels during angiogenesis in vitro.

Fibronectin is a component of the extracellular matrix of developing microvessels whose role in angiogenesis is poorly understood. This study evaluated the effect of plasma fibronectin on angiogenesis in serum-free collagen gel culture of rat aorta. Aortic explants embedded in collagen gels generated microvascular outgrowths. Fibronectin incorporated in the collagen gel promoted a selective dose-dependent elongation of the newly formed microvessels without stimulating vascular proliferation. The fibronectin-treated microvessels were longer due to a proportional increase in the number of microvascular cells. However, fibronectin had no effect on microvascular DNA synthesis and mitotic activity. Fibronectin stimulated microvascular length also in cultures in which mitotic activity was suppressed and angiogenesis was markedly reduced by pretreating the aortic explants with mitomycin C. The synthetic peptide Gly-Arg-Gly-Asp-Ser (GRGDS), which competes for the binding of fibronectin to its cell receptors and inhibits the adhesion of endothelial cells to substrates, arrested the elongation of developing microvessels causing regression and inhibition of angiogenesis. Conversely, Gly-Arg-Gly-Glu-Ser (GRGES), which lacks the RGD sequence, had no inhibitory effect. These data support the hypothesis that fibronectin promotes angiogenesis and suggest that developing microvessels elongate in response to fibronectin as a result of an adhesion-dependent migratory recruitment of endothelial cells that does not require increased cell proliferation.

Amino Acid Sequence↗
PubMed2003

Angiogenesis in wound repair: angiogenic growth factors and the extracellular matrix.

Angiogenesis is critical to wound repair. Newly formed blood vessels participate in provisional granulation tissue formation and provide nutrition and oxygen to growing tissues. In addition, inflammatory cells require the interaction with and transmigration through the endothelial basement membrane to enter the site of injury. Angiogenesis, in response to tissue injury, is a dynamic process that is highly regulated by signals from both serum and the surrounding extracellular matrix (ECM) environment. Vascular endothelial growth factor, angiopoietin, fibroblast growth factor, and transforming growth factor beta are among those most potent angiogenic cytokines in wound angiogenesis. The cooperative regulation of them is essential for wound repair. Migration of endothelial cells and development of new capillary vessels during wound repair is dependent on not only the cells and cytokines present but also the production and organization of ECM components both in granulation tissue and in endothelial basement membrane. The ECM regulates angiogenesis by providing scaffold support and signaling roles. They also serve as a reservoir and modulator for growth factors. Laminins are the major noncollagenous ECM of endothelial basement membrane. Two newly recognized laminins, 8 and 10, are the major laminins produced by human dermal microvascular endothelial cells. Laminin 10 is highly expressed in blood vessels around skin wounds. Laminin 8 promotes dermal endothelial cell attachment, migration, and tubule formation. Integrins with either beta 1 or alpha v subunits are the major cellular surface receptors for ECM molecules and mediate the interactions between cells and ECM during wound angiogenesis.

Cytokines↗
PubMed2005

Pododermal angiogenesis and angioadaptation in the bovine claw.

Pododermal microvascularization has been suggested to play a key role in the physiological function of the bovine claw and in the pathogenesis of claw diseases. According to our working hypothesis, angiogenesis plays a central role in the physiological and pathological function of the claw and is induced by the pro-angiogenic vascular endothelial growth factor (VEGF). As a basis for further research, the aim of the present study was to examine the mechanisms of pododermal angiogenesis in the functional adaptation of the microvasculature of the claw in histological serial sections and microcorrosion casts of healthy juvenile and adult claws as well as pathologically altered claws. Scanning electron microscopy of microcorrosion casts allowed assessment of the 3D aspect of pododermal angiogenesis and angioadaptation, and was substantiated by a concomitant examination of a 3D in vitro model of angiogenesis based on cultured bovine microvascular endothelial cells. Particularly in the juvenile, but also in the adult claw, sprouting and intussusceptive angioadaptation was demonstrated and resembled the respective stages of in vitro angiogenesis. Evidence of angiogenic processes was also detected in the pathologically altered claws displaying symptoms of subclinical laminitis and/or the digital dermatitis complex. The detected angioadaptation was visible expression of the increased metabolic demands of the claw caused by the growing body weight load. Angiogenic remodeling of the pododermal angioarchitecture was also the connectional reparative principle in pathologically altered claws. Related research perspectives for prophylaxis and therapy of claw diseases are discussed.

Adaptation, Physiological↗
PubMed2004

Neutralization of the chemokine CXCL10 enhances tissue sparing and angiogenesis following spinal cord injury.

After spinal cord injury, there is a chemoattractant-mediated inflammatory response that is associated with secondary degeneration. The chemoattractant CXCL10 recruits CD4 Th1 cells via the CXCR3A receptor and inhibits growth and chemotaxis of endothelial cells via the CXCR3B receptor. To test the hypothesis that CXCL10 inhibits angiogenesis following spinal cord injury, we assayed the brainstems and spinal cords of spinal cord-injured mice treated with anti-CXCL10 antibodies for expression of angiogenesis-associated genes and quantified blood vessels within their spinal cords. Brainstem microarray analysis indicated eight angiogenesis-associated genes that had significantly higher expression levels in the treated mice than in the untreated mice. Ribonuclease protection assays of the spinal cords showed a significant increase in eight angiogenesis-associated genes in treated animals compared with untreated animals. Histological analysis of the spinal cords of treated and untreated mice showed a significant increase in the number of blood vessels in treated animals. We conclude that CXCL10 plays a critical role in vasculature remodeling following spinal cord injury and that angiogenesis is enhanced following anti-CXCL10 treatment of spinal cord injuries. Improved blood flow and oxygen supply to the injury site may contribute to the functional improvement associated with this treatment.

Animals↗
PubMed2006

Expression of chymase-positive cells in gastric cancer and its correlation with the angiogenesis.

BACKGROUND AND OBJECTIVES: Chymase is expressed in mast cells and induces angiogenesis via activation of angiotensin II and matrix metalloproteinase-9. However, it has been unclear whether chymase is involved in the pathophysiology of angiogenesis in gastric cancer. To clarify the contribution of chymase to angiogenesis in gastric cancer, we assessed the relationship between chymase-positive cells and tumor angiogenesis. METHODS: We evaluated chymase-positive cells and microvessels using anti-human chymase and anti-CD34 antibodies in 168 cases of gastric cancer, respectively. RESULTS: Chymase-positive cells in gastric tumor region were significantly higher than the cells in normal region. The number of chymase-positive cells in the undifferentiated type of gastric tumor region was significantly higher than the one in the differentiated type. Specimens from patients with advanced histological stages of disease had more chymase-positive cells than those with early-stage disease. There was a significant positive correlation between chymase-positive cells and microvessels in gastric cancer specimens. Postoperative survival curves revealed that patients with a high number of chymase-positive cells had a poor prognosis. CONCLUSIONS: These results suggest that accumulation of chymase-positive cells in gastric cancer may lead to an increase of tumor angiogenesis, and may contribute to tumor growth and progression.

Adult↗
PubMed2001

VEGFR-3 in adult angiogenesis.

Vascular endothelial growth factor receptor 3 (VEGFR-3, Flt-4), the receptor for vascular endothelial growth factors (VEGFs) C and D, is expressed on lymphatic endothelium and may play a role in lymphangiogenesis. In embryonic life, VEGFR-3 is essential for blood vessel development. The purpose of this study was to investigate whether VEGFR-3 is also involved in blood vessel angiogenesis in the adult. This was studied in human tissues showing angiogenesis and in a model of VEGF-A-induced iris neovascularization in the monkey eye, by the use of immunohistochemistry at the light and electron microscopic level. VEGFR-3 was expressed on endothelium of proliferating blood vessels in tumours. In granulation tissue, staining was observed in the proliferative superficial zone in plump blood vessel sprouts, in the intermediate zone in blood vessels and long lymphatic sprouts, and in the deeper fibrous zone in large lymphatics, in a pattern demonstrating that lymphangiogenesis follows behind blood vessel angiogenesis in granulation tissue formation. At the ultrastructural level, VEGFR-3 was localized in the cytoplasm and on the cell membrane of endothelial cells of sprouting blood vessels and sprouting lymphatics. In monkey eyes injected with VEGF-A, blood vessel sprouts on the anterior iris surface and pre-existing blood vessels in the iris expressed VEGFR-3. In conclusion, these results support a role for VEGFR-3 and its ligands VEGF-C and/or VEGF-D in cell-to-cell signalling in adult blood vessel angiogenesis. The expression of VEGFR-3 in VEGF-A-induced iris neovascularization and in pre-existing blood vessels exposed to VEGF-A suggests that this receptor and possibly its ligands are recruited in VEGF-A-driven angiogenesis.

Animals↗
PubMed1995

Inhibition of tumor angiogenesis and the therapeutic ability of linomide against rat prostatic cancers.

Linomide, a quinoline-3-carboxamide, has growth-inhibitory effects against a series of Dunning R-3327 rat prostatic cancers in vivo [Ichikawa et al.: Cancer Res 52:3022-3028, 1992]. In addition, we have demonstrated that daily linomide treatment can inhibit angiogenic responses in nontumor-bearing rats and reduce tumor blood flow in tumor-bearing rats [Vukanovic et al.: Cancer Res 53:1833, 1993]. In the present study we have demonstrated that the reduced tumor blood flow is due to linomide's ability to inhibit tumor angiogenesis, as documented by decreased number of blood vessels in prostatic carcinomas growing in rats treated daily with linomide. Due to linomide's ability to inhibit tumor angiogenesis, and since tumor angiogenesis is required not only for the growth of the primary cancer but also for its ability to metastasize, the effect of linomide on metastasis was directly tested using a quantitation metastasis assay. These in vivo experiments demonstrated that daily linomide treatment decreased by 3-fold the extent of dissemination of cancer cells to the lungs. To test if this antimetastatic response is due to direct effects of linomide on the metastatic cells themselves as well as an induced effect upon inhibition of tumor angiogenesis, additional studies were performed. These studies demonstrated that linomide is not converted in vivo to metabolite(s) which are directly cytotoxic or cytostatic to the prostatic cancer cells themselves. These studies also demonstrated that linomide does not decrease the attachment, migration, or invasive abilities of metastatic cancer cells. These results suggest that the major mechanism for the antitumor and antimetastatic effects of linomide is via its inhibition of tumor angiogenesis. Additional studies have demonstrated that in vivo linomide treatment results in the apoptotic death of thymocytes. This cytotoxic effect is not required for linomide's antitumor effect, nor is it due to elevated plasma levels of glucocorticoid.

Alkylation↗
PubMed1998

Induction of in vitro angiogenesis in the endothelial-derived cell line, EA hy926, by ethanol is mediated through PKC and MAPK.

We have previously shown that ethanol-induced injury to the gastric mucosa triggers increased expression of the angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and angiogenesis. To further investigate ethanol-induced angiogenesis, we used an in vitro angiogenesis model which employs the ability of an endothelial-derived cell line (EA hy926) to form tubelike structures resembling capillaries when plated on the matrix material, Matrigel. We report that serum-starved EA hy926 cells, incubated for as little as 5 minutes with ethanol concentrations of 1.0-2.5%, formed tubelike structures reflecting in vitro angiogenesis. Control cells, not incubated with ethanol, did not form tubelike structures. Incubation for 5 minutes with 2.5% ethanol resulted in increased activities of PKC and MAP kinase (ERK2) by 1.6-fold (p < 0.05) and 2.3-fold (P < 0.001), respectively. Furthermore, inhibitors of the MAPK kinase, MEK (PD98059) and PKC (GF 109203X) prevented the induction of in vitro angiogenesis by ethanol.

Cell Line↗
PubMed1999

Apolipoprotein(a), a link between atherosclerosis and tumor angiogenesis.

Lipoprotein (a) [Lp(a)] is a LDL-like particle with one apolipoprotein(a) [apo(a)] covalently bound to apolipoprotein B, the structural protein of Low Density Lipoprotein (LDL). Lewis Lung Carcinoma (LL/2) cells exhibited delayed growth and reduced angiogenesis in apo(a) transgenic mice, expressing a recombinant apo(a) [r-apo(a)] with 18 kringle 4 repeats. The mean microvessel density of subcutaneous LL/2 tumors from apo(a) transgenic mice was significantly lower than that of tumors from control wild type mice. CHO cells secreting a truncated apo(a) protein with only six kringle 4 repeats did not exhibit delayed tumor growth nor did it impair angiogenesis. These data point to an unappreciated role of human apo(a) in angiogenesis and cancer biology. As angiogenesis is necessary for reendothelialization following vascular injury, suppression of angiogenesis by apo(a) may also contribute to the atherogenicity of apo(a). The differences between the truncated apo(a) and r-apo(a) are consistent with the higher atherogenicity of higher molecular weight isoforms.

Animals↗
PubMed2000

Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis.

The hepatitis B virus (HBV)-encoded transcriptional activator HBV-X protein (HBx) was known to be involved in hepatocarcinogenesis. Hepatocarcinogenesis generally included an active angiogenesis that was mainly considered to be due to a local hypoxia in liver tissues. However, the exact mechanisms of HBx-induced hepatocarcinogenesis were poorly understood. In this study, we examined the role of HBx in the increased angiogenesis and the possible regulating mechanisms of HBx by hypoxia. We demonstrated that HBx stimulated the transcription of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in HBx-stable transfectants. HBx-induced angiogenesis was confirmed by in vivo tumor angiogenesis assay, resulting in that the HBx transfectants increased the formation of new blood vessels compared to the control transfectants. Then, we demonstrated that the expression of HBx was enhanced after incubating HBV-infected hepatoma cells under hypoxia. Moreover, the activity of HBV enhancer 1 (Enh1) was increased when hepatoma cells transfected with the reporter plasmid containing HBV Enh1 were exposed to hypoxic conditions. These results strongly suggest that HBx may play a critical role in the hypoxia-induced angiogenesis through transcriptional activation of VEGF during hepatocarcinogenesis.

Cell Hypoxia↗
PubMed2001

Homocysteine inhibits angiogenesis in vitro and in vivo.

Homocysteine has been reported to inhibit endothelial cell proliferation, which is closely related to angiogenesis. However, the relationship between homocysteine and angiogenesis is unknown. To clarify whether homocysteine would inhibit angiogenesis in vitro and in vivo, we examined the effect of homocysteine on tube formation by bovine aortic endothelial cells (BAECs) and by human microvessel endothelial cell-1 (HMEC-1) in vitro, and on angiogenesis in vivo using the chorioallantoic membrane (CAM) assay, as well as on BAEC proliferation and migration. Homocysteine, but not cysteine, inhibited BAEC proliferation, migration, and tube formation in a dose-dependent manner at concentrations from 0 to 10 mM. Homocysteine also inhibited tube formation by HMEC-1s. In these assay, 50% inhibition was induced by about 1 mM homocysteine. In the in vivo CAM assay, 0, 10, 100, 500, and 1000 microgram homocysteine induced an avascular zone by 0, 0, 16.7, 53.3 and 76.5%, respectively, also showing a dose-dependent effect. It was suggested that homocysteine inhibited angiogenesis by preventing proliferation and migration of endothelial cells.

Animals↗
PubMed1994

Modulation of angiogenesis in vitro by laminin-entactin complex.

Laminin is a cross-shaped glycoprotein whose inner cross-region binds to the glycoprotein entactin (nidogen) forming a stable complex extractable from basement membrane matrices with chelating agents. In this study we evaluated the effect of the laminin-entactin complex on angiogenesis in serum-free collagen gel culture of rat aorta. Laminin-entactin stimulated or inhibited angiogenesis depending on its concentration in the gel. Stimulatory concentrations of laminin-entactin (30 to 300 micrograms/ml) promoted an increase in the number and length of microvessels. A similar effect was observed with purified laminin. Elongation of microvessels was also obtained with the laminin fragments E1' and E8 and with entactin, all of which have binding sites for endothelial cells. By contrast the E4 fragment of laminin, which has no cellular binding sites, failed to promote microvascular elongation. Inhibitory concentrations of laminin-entactin (3000 micrograms/ml) allowed formation of only a few stubby endothelial sprouts. Laminin-entactin promoted dose-dependent stabilization of microvessels preventing their regression. Microvessels stabilized by laminin-entactin were surrounded by thick patches of basement membrane-like material, whereas untreated microvessels prone to regression had a highly attenuated basement membrane. The angiogenic effect of laminin-entactin was enhanced by exogenous bFGF. However, bFGF was unable to stimulate angiogenesis over control values when incorporated in gels containing a high concentration of laminin-entactin. Our results indicate that laminin and its supramolecular complex laminin-entactin play an important modulatory role in angiogenesis. The dose-dependent effects of the laminin-entactin complex suggest that the basement membrane is a dynamic regulator of angiogenesis whose function varies depending on the concentration of its molecular components.

Animals↗
PubMed1994

Modulation of human fibroblast activity by selected angiogenesis inhibitors.

Tenon's fibroblast (TF) bleb encapsulation is a common cause of filtering surgery failure. Various pharmacologic agents have been used in an attempt to inhibit this response. The effects of three angiogenesis inhibitors were studied. AGM-1470, a fumagillin analog and hydrocortisone 21-phosphate (HC21P) complexed with heparin or with the heparin analog beta-cyclodextrin tetradecasulfate (BCD-TDS) in modulating human tenon's fibroblasts in cell culture. It has been clinically demonstrated that well vascularized blebs are associated with a poorer prognosis. In addition to reducing bleb neovascularization, angiogenesis inhibitors may have an additional therapeutic role in decreasing fibroblast activity. Drug effects were assessed by studying cell growth rates by cell Coulter counting and rate of wound closure. TF's were grown in DMEM with 10% FBS and 1% PCN-strep with fungizone. Angiogenesis inhibitors were added to growth medium in varying concentrations: AGM-1470 alone, HC21P complexed with heparin and HC21P complexed with BCD-TDS. Controls were grown in control medium alone, medium with added ethanol, or with added BCD-TDS, heparin or HC21P. We found a dose related inhibition of cell growth with all of the angiogenesis inhibitor combinations, which was not seen in the control groups. Tenon's fibroblast proliferation was significantly inhibited by AGM-1470 as seen in the four higher concentrations (P < 0.05) with insignificant inhibition at the lowest concentration of AGM-1470 (P = 0.38). The heparin:HC21P and heparin:BCD-TDS combinations demonstrated significant inhibition at all concentrations (P < 0.05). Wound closure was significantly inhibited by all the added agents, except AGM-1470 and the controls. The rate of wound closure was significantly reduced by the highest concentrations of the heparin:HC21P and heparin:BCD-TDS combinations (P < 0.05), although it was not significantly affected by lower concentrations (P > 0.05). Rank order of potencies of these agents for inhibition of TF proliferation was AGM-1470, BCD-TDS:HC21P, heparin:HC21P, HC21P, while the rank order of potencies for these agents for inhibition of wound closure was HC21P, heparin:HC21P, BCD-TDS:HC21P, AGM-1470. These selected angiogenesis inhibitors appear to have marked inhibitory effects on TF proliferation and migration, which may have a potential clinical role in modulating wound healing associated with glaucoma filtering surgery.

Cell Division↗
PubMed1998

Despite its homology to angiostatin apolipoprotein(a) does not affect angiogenesis.

Apolipoprotein(a) [apo(a)] contains a kringle domain(IV) homologous to that of angiostatin, a natural angiogenic inhibitor. Because of this structural similarity we suspected that apo(a) could be an inhibitor of angiogenesis. The possible role of apo(a) in microvascular proliferation was studied in an in vivo quantitative model, the disc angiogenesis system (DAS) and compared to angiostatin. Apo(a) and other test compounds were placed in the center of a polyvinyl alcohol foam disc that was implanted subcutaneously in mice. After 14 days, the disc was removed and vascular growth into the disc was measured. Apo(a) did not affect spontaneous vessel growth into the disc, while angiostatin suppressed this growth and basic fibroblast growth factor (bFGF) increased it. Additionally, apo(a) did not modify the vascular growth induced by bFGF. Transgenic mice expressing the human apo(a) gene were used to study the systemic effect of apo(a): neither an increase nor a decrease in vascular growth was detected. Our results suggest that apo(a) is unlikely to play a significant role in the control of angiogenesis. Furthermore, our experiments confirm the inhibitory effect of angiostatin not only on induced angiogenesis but also on baseline, spontaneous angiogenesis.

Angiostatins↗
PubMed2000

Wound healing: captopril, an angiogenesis inhibitor, and Staphylococcus aureus peptidoglycan.

BACKGROUND: Captopril, an angiotensin-converting enzyme inhibitor, used for treating hypertension and heart failure, inhibits angiogenesis in the corneas of rats in response to basic fibroblast growth factor, slows the growth of experimental tumors in rats, and leads to the regression of Kaposi's sarcoma. Because angiogenesis is key to wound healing, we hypothesized that captopril would impair wound healing. We hypothesized also that because local application at operation of Staphylococcus aureus peptidoglycan (SaPG) increases angiogenesis and accelerates wound healing in rats, SaPG would prevent or ameliorate the postulated captopril-impaired wound healing. MATERIALS AND METHODS: In each experiment, rats were divided randomly into two groups: one drinking tap water, and the other, tap water containing 0.5 mg captopril/ml. All ate chow and drank ad libitum, pre-operatively (4-12 days) and postoperatively (7 days). In experiments 1 and 2, bilateral paravertebral 5.5-cm skin incisions were made aseptically (intraperitoneal sodium pentobarbital), and closed with interrupted No. 35 stainless-steel sutures. On one side, the wound was immediately inoculated with 157 microliter pyrogen-free isotonic saline and on the other side the wound was inoculated with 157 microliter saline containing 4.7 mg SaPG (860 microgram SaPG/cm incision). In the third experiment, polyvinyl alcohol (PVA) sponges (16-17 mg dry wt each) containing either 50 microliter saline or 0.5 mg SaPG in 50 microliter saline were implanted subcutaneously, two on each side, via 1-cm incisions closed with a single suture. In the fourth experiment, 5.5-cm bilateral skin incisions and subcutaneous implantation of PVA sponges were done as described but all sites were instilled with saline only. All rats were euthanized (CO(2) asphyxia) 7 days postoperatively. RESULTS: Wound breaking strength (WBS) of the saline-treated incisions was significantly higher (P < 0.001) in captopril-treated rats than in controls (172 +/- 13 g vs 105 +/- 6 g) in experiment 1 and higher, but not significantly in captopril-treated rats in experiment 2 (153 +/- 8 g vs 114 +/- 6 g) (PNS). SaPG inoculation of the incisions increased WBS significantly in both control and captopril-treated rats: 187 +/- 11 g vs 105 +/- 6 g (P < 0.001) and 283 +/- 16 g vs 172 +/- 13 g (P < 0.001), respectively, in experiment 1, and 217 +/- 13 g vs 114 +/- 6 g (P < 0.0001) (controls) and 266 +/- 17 g vs 153 +/- 8 g (captopril-treated rats) (P < 0.0001) in experiment 2. In experiment 3, subcutaneous PVA saline-inoculated sponge reparative tissue hydroxyproline (OHP) content was similar in control and captopril-treated rats, and SaPG inoculation increased reparative tissue OHP significantly in both groups: 2458 +/- 218 microgram/100 mg dry sponge vs 3869 +/- 230 microgram/100 mg (P < 0.001) (controls) and 2489 +/- 166 microgram/100 mg vs 4176 +/- 418 microgram/100 mg (P < 0.001) (captopril-treated rats). Histologically, angiogenesis and reparative tissue collagen were similar in control and captopril-treated rats, in both saline-inoculated and SaPG-inoculated sponges. In experiment 4 (all incisions and subcutaneous PVA sponges were saline-inoculated), there was no significant difference in WBS between control and captopril-treated rats (107 +/- 6 g vs 96 +/- 5 g, NS). PVA sponge reparative tissue OHP was significantly higher in captopril-treated rats: 3698 +/- 170 microgram/100 mg dry sponge vs 2534 +/- 100 microgram/100 mg (P < 0.0001). CONCLUSION: Unexpectedly, in four experiments, captopril did not inhibit WBS or PVA sponge reparative tissue angiogenesis or collagen accumulation; in fact, WBS was increased significantly in one of three experiments, and PVA sponge reparative tissue OHP was increased significantly in one of two experiments. Also, captopril did not interfere with the wound healing-accelerating effect of SaPG.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Suramin analogs inhibit human angiogenesis in vitro.

BACKGROUND: Suramin is a polysulfonated naphthylurea that inhibits tumor cell proliferation and angiogenesis, but the widespread use of this drug has been limited by significant neurologic toxicity. A series of suramin analogs that may exhibit less toxicity in vivo have been synthesized. We hypothesized that these novel analogs would have antiangiogenic properties equal to or greater than those of suramin when evaluated in an in vitro human placental vein angiogenesis model. METHODS: Human placental veins (n = 72 per group) were cultured in a 0.3% fibrin clot for a period of 14 days. Three suramin analogs (NF 145, NF 248, NF 293) and suramin were tested at 56 and 560 microM concentrations to determine their effect on the development of an angiogenic response. Experiments were repeated for each analog on veins from three different placentas. The percentage of wells that initiated an angiogenic response was calculated and compared with initiation in a control group (n = 141). RESULTS: The three suramin analogs inhibited angiogenesis in a dose-dependent fashion, with all compounds exhibiting near-complete inhibition of angiogenesis at 560 microM. The effects of these analogs were equal to or greater than those of suramin. CONCLUSION: Suramin analogs with structural alterations inhibit human angiogenesis at concentrations equivalent to those seen in vivo. These analogs may be more effective antiangiogenic agents than suramin and may have less potential for toxicity.

Animals↗
PubMed1994

Basic fibroblast growth factor and de novo mammalian angiogenesis.

Using the rat mesenteric-window assay, the de novo angiogenic effect of basic fibroblast growth factor (bFGF) in the intact, adult, normally vascularized test tissue was analyzed using quantitative microscopy including image analysis. Basic FGF was injected ip at doses of 10, 100, and 1000 ng twice daily for 4.5 days and the animals, which were not subjected to surgery, were sacrificed in groups every week for 6 consecutive weeks. The scale and dynamics of the angiogenic response were measured in terms of variables related to microvascular spatial expansion and density. The growth factor-induced angiogenesis in a dose-dependent, nonlinear manner and the angiogenesis displayed distinctly dose-dependent kinetics. The middle dose thus caused angiogenesis that peaked already at Day 7, thereby suggesting a direct effect. The high dose caused angiogenesis that peaked at Day 14, which also appears to be compatible with a direct effect. The low dose caused a more prolonged angiogenic response which did not peak until Day 21 or 28, depending on which variable was measured, which is indicative of an indirect effect. Clearly, the findings suggest that the molecular and cellular mechanisms of bFGF-mediated angiogenesis are dose-dependent.

Animals↗