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PubMed2001

Tumor vascularity: a histological measure of angiogenesis and hypoxia.

In this study we sought to clarify the relationship between tumor vascularity, hypoxia, and angiogenesis in human cervix tumors. Two hypotheses were established: first, that measurement of tumor vascularity can provide a histological assessment of both hypoxia and angiogenesis; and second, that expression of angiogenesis-related proteins will provide a surrogate measure of tumor hypoxia. To test the first hypothesis, we studied the prognostic significance of tumor vascularity measured as both intercapillary distance (ICD; thought to reflect tumor oxygenation) and microvessel density (MVD; the hotspot method that provides a histological assessment of tumor angiogenesis). The relationship was also examined of tumor hypoxia, measured using an Eppendorf needle electrode [percentage of values less than 5 mm Hg (HP5)], with ICD and MVD. To test the second hypothesis we examined the relationship between HP5 and the expression of angiogenesis-associated proteins [vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF)]. All of the biological measurements were made on pretreatment tumors. Analysis of data was carried out using log-rank statistics, Cox multivariate analysis, and Spearman's rank correlation. Both ICD and MVD were significant independent prognostic factors for local control. Patients with poorly vascularized tumors (long ICD) had poor local control (P = 0.042). However, patients with poorly vascularized tumors, measured as low MVD, had good local control (P = 0.036). For 107 patients in whom both of the measurements were obtained on the same tumor sections, ICD and MVD provided independent prognostic information in multivariate analysis. There was a significant correlation between tumor hypoxia and ICD (P < 0.005) but not MVD (P = 0.41). There was no relationship between hypoxia and the expression of angiogenic factors (VEGF, PD-ECGF). These analyses show that measurement of tumor vascularity can provide different biological information that is dependent on the method used. It is, therefore, important that studies measuring vascularity should include an appropriate definition. There is no relationship between hypoxia and angiogenesis in advanced carcinoma of the cervix and examining the levels of angiogenic proteins may not have a role in assessing hypoxia in cervix cancer.

Cell Hypoxia↗
PubMedDate not supplied

Angiogenesis and endometrial cancer.

Angiogenesis occurs more frequently in endometrial carcinomas developing against a background of endometrial atrophy rather than carcinomas arising from a hyperplastic endometrium. In some studies, angiogenesis is associated with unfavourable histopathological features, but not in others. In all studies, however, increased angiogenesis is related to poor prognosis. Vascular endothelial growth factor (VEGF) is the major stimulus for endothelial cell proliferation in endometrial carcinomas and is, therefore, associated with high angiogenesis. VEGF expression at the invading tumour front is 4-10 times higher than in the inner tumour areas and is significantly associated with poor prognosis, particularly within stage I endometrial disease. However, since its stimulating effect on endothelial cells is basically dependent on the presence of VEGF receptors, i.e. the flk-1(KDR), the detection of a functionally intact angiogenic pathway VEGF/flk-1 (KDR) is a more reliable and, indeed, independent prognostic parameter. The other angiogenic factor, thymidine phosphorylase (TP), is related to the adverse histopathological variables of the non endometrioid carcinomas, high tumour grade, deep myometrial invasion and advanced stage of disease, at least at the invading tumour front, and its prognostic significance is, therefore, limited. Furthermore, it is not directly related with increased angiogenesis. However, the simultaneous expression of high VEGF / high TP activity at the invading tumour front emerged as the most potent angiogenic phenotype in endometrial carcinomas, indicating that the two molecules are co-operating. Furthermore, a high TP activity in the stromal cells is associated with a high density of activated macrophages which further promotes endometrial tumour angiogenesis.

Animals↗
PubMedDate not supplied

Non-sprouting angiogenesis in neurohypophysis after traumatic injury of the cerebral cortex. Electron-microscopic studies.

OBJECTIVES: Angiogenesis comprises two different mechanisms: endothelial sprouting and intussusceptive microvascular growth. The sprouting process is based on endothelial cell migration, proliferation and tube formation. Intussusceptive microvascular growth divides existing vessel lumens by formation and insertion of endothelial columns into the vessel lumen. The morphological features of microvessels of cerebral cortex and neurohypophysis were evaluated in a model of the cerebral traumatic injury. METHOD: The observations were conducted seven days after induction of cortical trauma. Traumatic injury was induced in the fronto-temporal region of cerebral cortex in general anesthesia with 20mg/kg ketamine hydrochloride. RESULTS: Seven days after traumatic brain injury in sections from cerebral cortex and neurohypophysis we can observe morphological features of angiogenesis. Endothelium of the cerebral cortex possesses high endotheliocytes tightly connected and enveloped by amorphous basement membrane-like material. Transcapillary pillars tightly connected with neighbouring endothelial cells split the newly formed vessels and branching takes place. In neurohypophysis we can observe all stages of non-sprouting angiogenesis: proliferation endothelial cells on the inside mother vessel, splitting newly formed blood vessels by transcapillary pillars directed into the vessel lumen, maturation of endothelium and network formation. CONCLUSION: The mechanical injuries directly induced angiogenesis not only in cerebral cortex, but also in neurohypophysis. Our studies show that mechanism of angiogenesis is not the same as observed previously in neurohypophysis after focal cerebral ischemia (Neuroendocrinology Letters 2001; 22:87 92). This study indicates that mechanism of angiogenesis can depend on kind of induction.

Animals↗
PubMed2003

Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor.

PURPOSE: The purpose of this study was to evaluate the feasibility of incorporating a novel wound angiogenesis assay into a Phase I study of BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor, and to determine whether the wound angiogenesis assay was able to detect the inhibition of angiogenesis in patients treated with BMS-275291. EXPERIMENTAL DESIGN: Before treatment began, a 4-mm skin biopsy was performed. The wound was imaged for 14 days. Treatment was started on day 0, and a separate 4-mm biopsy was performed 14 days later. The second wound was also imaged for 14 days. Wound angiogenesis was scored by two independent observers who were blinded to treatment status. RESULTS: The median times in days (95% confidence interval) to reach the target average vascular score (AVS) of 1.5 and 2.0 based on the data of Observer 1 were 3.7 (2.2-6.9) and 8.0 (5.0-10.0) pretreatment whereas on-treatment the values were 4.9 (3.7-8.0) and 9.3 (7.0-11.5), respectively. The delay in the median time to reach an AVS of 1.5 was 1.2 days or a 32% reduction when comparing pretreatment with on-treatment (P = 0.06). For the target AVS of 2.0 the delay in the median time pretreatment versus on-treatment was 1.3 days or a 16% reduction (P = 0.04). CONCLUSIONS: The wound angiogenesis assay used in this study was practical, well tolerated, and reproducible. Delays in wound angiogenesis because of BMS-275291 were detectable with this assay. This technique warrants additional investigation in clinical trials of other antiangiogenic agents.

Antineoplastic Agents↗
PubMed2003

Thymidine phosphorylase-mediated angiogenesis regulated by thymidine phosphorylase inhibitor in human ovarian cancer cells in vivo.

Metastasis or progression of ovarian cancer cells is known to be due to the action of various angiogenic factors. We determined the expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) and vascular endothelial growth factor (VEGF) in cell lines established from 3 serous adenocarcinomas, 3 clear cell carcinomas and 2 mucinous carcinomas of the human ovary. TP activity and the TP mRNA level were much higher in the serous adenocarcinoma cells than in the clear cells and mucinous carcinoma cells, and TP expression was extremely low in the clear cell carcinoma cells. Expression of VEGF mRNA was variable, but not significantly different between the 3 histological types of ovarian cancer. In vivo angiogenesis in the ovarian cancer cells was evaluated by the dorsal air sac assay and revealed that SHIN-3 and HRA serous adenocarcinoma cells, which have high levels of TP expression, induced angiogenesis, while KK clear cell carcinoma cells with low TP expression, did not. The degree of ovarian-cancer-induced angiogenesis seemed to be independent of expression of VEGF in the cells. To confirm that the serous adenocarcinoma-induced angiogenesis is dependent on TP levels, a potent and specific inhibitor of TP was administered orally to mice implanted with a chamber containing SHIN-3 or HRA cells. The TP inhibitor significantly inhibited the angiogenesis induced by the serous adenocarcinoma cells. These results suggest that the angiogenic potency of ovarian cancer cells differs with the histological type and is controlled by expression of TP/PD-ECGF, not by VEGF, and that TP-mediated angiogenesis may be the main factor responsible for progression or metastasis of ovarian serous adenocarcinomas.

Adenocarcinoma, Clear Cell↗
PubMed1992

Angiogenesis can be stimulated or repressed in vivo by a change in GM3:GD3 ganglioside ratio.

BACKGROUND: We had previously observed that rabbit cornea stimulated by an angiogenic factor 1) became richer in total gangliosides and 2) reduced the GM3:GD3 ganglioside ratio. Moreover, experimentally induced global enrichment of corneal gangliosides favors angiogenesis. EXPERIMENTAL DESIGN: The objective of this work was to explain the possible relationship between angiogenic response and changes in the GM3:GD3 ratios observed in vivo. Cornea was utilized because it is avascular and transparent; i.e., the onset of opacity permitted exclusion of angiogenesis produced by a generic inflammatory response. Prostaglandin E1 or basic fibroblast growth factor were applied as angiogenesis triggers. Angiogenesis in vivo and mobilization and growth of microvascular endothelium in vitro were taken as parameters to indicate whether differences in GM3:GD3 ratios could modify the extent of the angiogenic response. RESULTS: In vivo angiogenesis, whether prostaglandin E1 or basic fibroblast growth factor induced, was repressed by GM3 and enhanced by GD3 or GM1 enrichment of the cornea. In vitro growth and motility of microvascular endothelium were reduced by GM3 addition to the medium and returned to normal levels by addition of GD3. CONCLUSIONS: Formation of new vessels induced by two different angiogenic factors could be stimulated or repressed in the cornea by reduction or enhancement of the GM3:GD3 ratio of tissue gangliosides. Changes in the relative proportion of molecules normally present in adult tissues, like prostaglandin E1, basic fibroblast growth factor, GM3, GD3, were sufficient to modulate or even block angiogenesis.

Alprostadil↗
PubMed1992

Inhibition of angiogenesis.

The concept of antiangiogenic therapy was first proposed in the early 1970s as a method of restricting tumor growth by inhibiting angiogenesis. In subsequent years sufficient knowledge about the process of angiogenesis itself was obtained so that it is now possible to begin to develop antiangiogenic therapy for clinical use. At least three strategies are feasible: (i) inhibition of release of angiogenic molecules from tumor cells; (ii) neutralization of angiogenic molecules that have already been released; and (iii) inhibition of vascular endothelial cells from responding to angiogenic stimulation. Most of the angiogenic inhibitors that have been discovered at the time of writing, directly interfere with the ability of endothelial cells to form new capillary blood vessels. Antiangiogenic activity is a newly found property of alpha-interferon. Although alpha-interferon is a relatively weak angiogenesis inhibitor in comparison to others, it has been very successful in the treatment of life-threatening hemangiomas in children. Early clinical experience with this first angiogenesis inhibitor to reach clinical trial, indicates that optimal antiangiogenic therapy in the future is likely to be based on the long-term use of inhibitors with low toxicity, and with little chance of inducing drug-resistance. It is apparent that different types of angiogenesis inhibitor may be administered together and that these compounds may also be administered to cancer patients as adjuncts to conventional chemotherapy. It is important to recognize that tumor vasculature has other properties besides angiogenesis, which make it a potential specific target for anti-cancer therapy.

Animals↗
PubMed2003

Effect of octreotide on angiogenesis induced by hepatocellular carcinoma in vivo.

OBJECTIVE: To investigate the effect of somatostatin analogue octreotide on angiogenesis induced by hepatocellular carcinoma (HCC) in vivo. METHODS: LCI-D20 corneal micropocket model in nude mouse was used to dynamically observe angiogenesis under a stereoscopic zoom microscope and a digital camera system and to evaluate the effect of octreotide on angiogenesis. Male nude mice were subcutaneously implanted with LCI-D20 tumor tissues for tumor xenograft studies. Microvessel density in CD34-stained tumor sections was analyzed by immunohistochemical SP method. RESULTS: Tumor tissues from LCI-D20 implanted into the corneal micropocket induced angiogenesis. When animals received systemic octreotide treatment, angiogenesis response in the cornea of mice was moderate, the appearance of vascular buds was delayed, and the new capillaries were sparse and grew slowly. Compared with the control group, the neovascularization induced by HCC in the cornea of mice was markedly inhibited on day 7, 9, 12, 15, 18 and 21 after implantation in the octreotide-treated group (P<0.05). Systemic administration of octreotide produced a significant suppression of the growth of LCI-D20. Immunohistochemical studies of tumor tissues revealed decreased microvessel density in the octreotide-treated animals as compared with the controls (21.7+/-4.27 versus 31.8+/-3.87, P<0.01). CONCLUSION: Somatostatin analogue octreotide is able to inhibit angiogenesis induced by HCC in vivo and may provide a new approach to the treatment of HCC.

Animals↗
PubMed2004

Overexpression of cathepsin B correlates with angiogenesis in colon adenocarcinoma.

Some studies have shown the influence of proteases and vascular density in colorectal primary tumors on spreading and on the course of colorectal cancer. In the present study we have analyzed the relationships between overexpression of cathepsin B protein and angiogenesis intensity in resected colon tumors and their impact on prognosis. It has been investigated in a series of 90 colon cancer patients. Immunohistochemistry was used to evaluate cathepsin B overexpression in cancer cells and to visualize microvessels with antibodies against von Willebrand factor. Overexpression of cathepsin B was observed if more than 50% of cancer cells in searched field showed immunoreactivity with antibody against cathepsin B. Intensity of angiogenesis was evaluated as a mean number of microvessels from three fields with highest vessel number. In 36 cases (40%) overexpression of cathepsin B was detected. Increased angiogenesis (above median 31 vessels per 0.785 mm2) correlated positively with cathepsin B overexpression (p=0.0006). Higher vascular density associated with the presence of metastases in regional lymph nodes (p=0.01). Overexpression of cathepsin B was observed more often in group of older people (age above median 65 years; p=0.005). According to univariate analysis metastases in regional lymph nodes (p=0.0007), increased angiogenesis (p=0.0085), and distant metastases (p=0.02) were the features potentially influencing prognosis. Multivariate analysis revealed independent prognostic value only in case of metastases in regional lymph nodes (p=0.013) and when distant metastases were present (p=0.021), but not when increased angiogenesis in primary colon adenocarcinoma was observed (p=0.078). In conclusion we can say that there is a close relationship between intensity of angiogenesis and overexpression of cathepsin B protein in cancer cells in resected colon adenocarcinoma.

Adenocarcinoma↗
PubMed2004

[Role and mechanism of nuclear factor kappa B in angiogenesis of human ovarian carcinoma].

BACKGROUND & OBJECTIVE: It had been reported that nuclear factor kappa b (NF kappa B) was associated with in vitro angiogenesis, but its role in angiogenesis of human ovarian carcinoma (HOC) had not been reported yet. The objective of this paper was to investigate the role and the mechanism of NF kappa B in HOC angiogenesis in chick chorioallantcic membrane (CAM). METHODS: The HOC TYK cells were implanted into 10-day CAM by 1 x 10(9)/per egg to establish the HOC CAM model. (1) With 20 eggs, the levels of NF kappa B, integrin alpha V beta 3, basic fibroblast growth factor (bFGF) at 0 h, 6 h, 12 h, 24 h, 48 h, 72 h time point after cells implanted were determined with ELISA. (2) The relationship among NF kappa B, bFGF,alpha V beta 3 and the effect of them on HOC angiogenesis in CAM were determined. Another 80 eggs were divided into 6 groups, normal saline (NS) (control group, 16 eggs), anti- NF kappa B (A group, 16 eggs), anti-bFGF (B group, 16 eggs), anti-NF kappa B + anti-bFGF(D group, 8 eggs) were added respectively into CAM at 6h time point after the cells implanted, and then anti-integrin alpha V beta 3 (C group, 16 eggs), anti-NF kappa B +anti-alpha V beta 3 (E group, 8 eggs) antibodies were added at 12h time point. Eight eggs from NS, A, B, C groups were taken out to determine the levels of NF kappa B, alpha V beta 3, bFGF at 48 h after the antibodies were added. The other eggs were incubated up to 5 days, and the vessel area/area were determined with image analysis. RESULTS: (1)The levels of NF kappa B and bFGF increased significantly at 6h, and that of V beta 3 increase significantly at 12 h time point after implantation (P< 0.01) (0.185+/-0.01, 0.771+/-0.16, 0.231+/-0.02), the peaks of the three levels were reached at 48 h (P< 0.01) (0.337+/-0.01, 1.639+/-0.01, 0.349+/-0.01). The levels of bFGF was significantly higher than those of NF kappa B and alpha V beta 3 at each time point (P< 0.01), but there were no significant difference between NF kappa B and alpha V beta 3 (P >0.05). (2)The levels of NF kappa B,bFGF, and alpha V beta 3 in A and B groups were significantly lower than those of NS group (P< 0.01) (0.098+/-0.02, 0.156+/-0.02, 0.329+/-0.01; 1.106+/-0.33, 0.412+/-0.01, 1.591+/-0.13; 0.138+/-0.03, 0.114+/-0.02, 0.322+/-0.01). And the level of alpha V beta 3 in C group were significantly reduced compared with those of NS group (P< 0.01) (0.119+/-0.02, 0.322+/-0.01), while the levels of NF kappa B and bFGF had no change between the two groups (P>0.05). The VA/A of the five groups of A, B, C, D, and E were significantly lower than that of NS group (P< 0.05) (26.10+/-13.71, 34.12+/-4.85, 25.50+/-11.41,14.32+/-3.11, 24.36+/-4.95, 66.62+/-17.64), and that of D group were significantly reduced compared with A group (P< 0.05) (14.32+/-3.11, 26.10+/-13.71), but there were no significant difference among the four groups of A, B, C, and E (P >0.05). CONCLUSIONS: NF kappa B can stimulate the angiogenesis of ovarian carcinoma with bFGF by upregulating the expression of alpha V beta 3, bFGF, which can be used as a marker of angiogenesis and a therapy target molecule of ovarian carcinoma.

Animals↗
PubMed2004

[Accelerated angiogenesis in artificial dermis with allogenic cultured dermal fibroblasts transplantation].

OBJECTIVE: To evaluate the effects of cryopreserved cultured allogenic dermal fibroblasts on angiogenesis and fibroplasia while artificial dermis grafting by spraying the cells on the graft bed. METHODS: Full thickness skin defect was made on the back of Wistar rat, fibroblasts mixed into fibrin glue (fibroblast group) and same amount fibrin glue (control group) were sprayed separately between the wound bed and artificial dermis in cell density of 1.0 x 10(5) cells/cm2 before the artificial dermis was grafted. On day 5 after grafting, the graft and surrounding tissue were examined histologically for angiogenesis and fibroplasia in the dermis and wound bed with hematoxylin eosin stain, VEGF antibody stain, Masson's trichrome stain and India ink stain. Evans blue perfusion method was also used for detecting the angiogenesis quantitatively. RESULTS: In the fibroblast group, the angiogenesis of graft bed was significantly accelerated on day 5 after grafting; the numbers of the newly formed capillaries were 9.64 +/- 2.36/HP in the fibroblast group and 3.88 +/- 1.62/HP in the control group (P < 0.05). And on day 10 after grafting the angiogenesis was accelerated not only in graft bed but also in the artificial dermis when compared with control group, the newly formed capillaries network was clearly observed in the artificial dermis. Otherwise, the synthesis of collagen was increased in the dermis on day 10 after grafting in the fibroblast group when compared with control group. The immunoreactivity of VEGF antibody in the fibroblast group also showed a stronger expression than that in control group on day 5 after grafting, the numbers of positive cells were 46.04 +/- 8.90/HP in the fibroblast group and 30.08 +/- 7.76/HP in the control group(P < 0.05). CONCLUSION: Transplantation of cryopreserved dermal fibroblasts while artificial dermis grafting can accelerate the angiogenesis and fibroplasia in the artificial dermis and graft bed, thereby accelerate the formation of dermal-like tissue in the artificial dermis.

Animals↗
PubMed2004

Evaluation of angiogenesis, p-53 tissue protein expression and serum VEGF in patients with endometrial cancer.

Endometrial carcinoma occurs mostly in post-menopausal women. Classical methods of prognostication, as FIGO stage and histopathologic grade, could be improved by applying additional techniques, utilizing molecular biology and immunochemistry. p-53 tumor suppressor gene, the most commonly mutated gene in human cancers has been shown to play an important role in the biology of gynecologic carcinomas. Angiogenesis, a process of formation of new vessels, being connected to tumors progression and metastatic potential was shown to be linked with tumor suppressor genes expression. The aim of the study was to evaluate relationships between intensity of tumor angiogenesis, serum levels of Vascular Endothelial Growth Factor (VEGF) and tissue p-53 protein expression in endometrial adenocarcinoma. Angiogenic Point's Density (APD) was calculated in hot spots areas using the morphometric appliance. For detection of p53 protein in tumor samples, LSAB + Kit Alkaline Phosphatase (DAKO) was used. VEGF levels were assessed in patient's blood sampled before the operation. Overexpression of p53 protein was found in tumor tissue in 35.2% of cases and mean angiogenic points density was greater in p53 positive cases. Serum levels of VEGF were above the cut off level in 54.5% of patients, in those cases angiogenesis was also elevated. In cases of p53 overexpression, VEGF levels tended to be greater as compared with p53 negative cases. In conclusion, our study demonstrated that angiogenesis was more intensive in p53 positive cases, confirming the hypothesis of tumor suppressor-gene regulation of the process of neovascularization. Serum levels of VEGF were borderline-significantly higher in cases of p53 overexpression, they were also correlated to the angiogenesis. Joint assessment of angiogenesis and tumor suppressor genes expression may contribute to reliable evaluation of the biology of endometrial carcinoma.

Adenocarcinoma↗
PubMed2005

Dynamics of changes in vascular endothelial growth factor (VEGF) expression and angiogenesis in stress-induced gastric ulceration in rats.

Angiogenesis and VEGF play a major role in many repair processes such as healing of gastric ulceration. The present study was undertaken to assess the dynamics of changes in VEGF expression and angiogenesis in stress-induced gastric ulcers in rats. Acute gastric ulceration was induced using a water-immersion and restraint stress method. The VEGF expression, angiogenesis, size of area and depth of ulcers in gastric specimens were evaluated. The study shows that as early as one day after the development of ulcers there is a significant increase in both the expression of the VEGF protein and the number of newly formed microvessels, while an abrupt decrease in VEGF expression, observed on the fifth day, results in a decreased intensity of angiogenesis. Moreover, it has been demonstrated that the increase in VEGF expression and angiogenesis is accompanied by a reduction in the size of area and depth of stress-induced ulcers in rats. Six days after ulcer development both VEGF expression and angiogenesis return to normal levels.

Animals↗
PubMed2005

[Inhibitory effects of Scutellaria barbatae D. Don on tumor angiogenesis and its mechanism].

BACKGROUND & OBJECTIVE: Various chemically synthetic anti-angiogenesis agents have serious side effects. The traditional Chinese medicine has attracted considerable attention because of its low toxicity. This study was to explore the inhibitory effects of Scutellaria barbatae D. Don, a kind of traditional Chinese medicinal anti-cancer herb, on tumor angiogenesis, and investigate its mechanism. METHODS: Matrigel plug and human umbilical vascular endothelial cells (HUVECs) were used to construct in vivo and in vitro models of angiogenesis to assess the effect of Scutellaria barbatae D. Don on angiogenesis. After cultured with Scutellaria barbatae D. Don, the migration of endothelial cells was examined by Transwell chamber; the expression of vascular endothelial growth factor (VEGF) in HeLa cells was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Scutellaria barbatae D. Don significantly inhibited angiogenesis in Matrigel; the tube formation number was significantly lower in 20% and 40% medicated serum groups containing Scutellaria barbatae D. Don than in 20% and 40% drug-free serum groups (5.6+/-1.1 vs. 9.8+/-1.3, P=0.001; 1.0+/-0.7 vs. 13.4+/-1.1, P<0.001). Migrated endothelial cells was significantly fewer in 20% and 40% medicated serum groups containing Scutellaria barbatae D. Don than in 20% and 40% drug-free serum groups (19.75+/-2.63 vs. 24.25+/-2.06, P=0.038; 14.00+/-2.58 vs. 26.5+/-4.65, P=0.006). When treated for 24 h and 48 h, the expression of VEGF in HeLa cells was significantly lower in 40% medicated serum group containing Scutellaria barbatae D. Don than in 40% drug-free serum group (138.67+/-9.50 vs. 195.82+/-2.43, P=0.006; 93.84+/-41.11 vs. 193.68+/-18.37, P=0.036). CONCLUSION: Scutellaria barbatae D. Don could efficiently inhibit angiogenesis in tumor tissue which might relate with inhibition of endothelial cell migration and down-regulation of VEGF in tumor cells.

Animals↗
PubMed2006

Assessing angiogenesis during fracture healing.

Angiogenesis, the sprouting of new capillaries from existing blood vessels, is crucial for normal fracture healing. Angiogenesis is a complex process involving a variety of growth factors and several cell types. The mechanism regulating angiogenesis during fracture repair is not well understood, and the relationships between angiogenesis, chondrogenesis, and osteogenesis are also undefined. In vivo animal models have been useful for determining angiogenic mechanisms. In particular, a murine model has been developed that offers the advantages of easy animal handling, low cost, reliable healing, and the availability of molecular and genetic techniques for research. However, the small size of mice provides challenges, including the inability to assess vascularization using techniques that have been employed in larger animals. Therefore, we developed and optimized techniques specifically for studying angiogenesis during mouse fracture repair. These techniques include blood vessel casting, micro-computed tomography (micro-CT), immunohistochemistry, in situ hybridization, and genetic labeling of endothelial cells. Blood vessel casting and micro-CT are useful for visualization of small blood vessels. Immunohistochemistry using anti-PECAM (platelet endothelial cell adhesion molecule) or CD34 antibodies and genetic approaches using Tie2-cre transgenic mice can be used to label endothelial cells, visualize blood vessels including capillaries, and provide structural information about the vascularization of the fracture callous. Lastly, expression patterns of important growth factors regulating angiogenesis could be assessed by molecular approaches such as in situ hybridization.

Animals↗
PubMed1990

Growth of microvessels in serum-free matrix culture of rat aorta. A quantitative assay of angiogenesis in vitro.

We report here that rings of rat aorta embedded in gels of fibrin or collagen and cultured in MCDB 131, an optimized growth medium for microvascular endothelial cells, generate branching microvessels in the absence of serum or other soluble protein supplements. The angiogenic response is self-limited and can be quantitated by counting the newly formed microvessels daily in the living cultures. The microvascular growth curves are characteristic for each gel. Growth of microvessels in collagen gel peaks at the end of the 1st week and is followed by a rapid regression in the 2nd week. Fibrin gels, as compared with collagen, stimulate angiogenesis by 170%, support growth during the 2nd week, and protect the newly formed microvessels from early regression. Angiogenesis is inhibited by adding hydrocortisone to the culture medium. Conversely, a 230% stimulation of angiogenesis is obtained when aortic rings are cultured in collagen gels floating in serum-free medium conditioned by sarcoma 180 cells. Our results demonstrate that: (a) angiogenesis can be obtained reproducibly in serum-free culture; (b) serum-free culture is a sensitive method for testing the inhibitory or stimulatory effects of soluble or matrix factors on angiogenesis; (c) the aortic ring model can be used as a quantitative assay for the study of angiogenesis under chemically defined culture conditions.

Animals↗
PubMed1991

Angiogenesis inhibition by minocycline.

We describe a new inhibitor of angiogenesis, minocycline, a semisynthetic tetracycline antimicrobial with anticollagenase properties. Minocycline was incorporated into controlled release polymers and tested in the rabbit cornea against neovascularization in the presence of the VX2 carcinoma. Inhibition by minocycline was shown to be comparable to that of the combination of heparin and cortisone, a potent inhibitor of angiogenesis. Minocycline decreased tumor-induced angiogenesis by a factor of 4.5, 4.4, and 2.9 at 7, 14, and 21 days, respectively. At the end of the experiment, whereas the corneas with empty polymers had large, invasive, exophytic tumors, none of the corneas with minocycline had such vascular masses. Recently, studies of agents that disrupt collagen synthesis and deposition have yielded several new angiogenesis inhibitors. We suggest that investigation of agents that disrupt collagenolysis may similarly identify other angiogenesis inhibitors and further clarify the mechanisms of angiogenesis.

Animals↗
PubMed1991

Inhibition of angiogenesis in vitro by Arg-Gly-Asp-containing synthetic peptide.

This study was designed to evaluate the effect of the synthetic peptide Gly-Arg-Gly-Asp-Ser (GRGDS) on angiogenesis in serum-free collagen gel culture of rat aorta. The GRGDS peptide contains the amino acid sequence Arg-Gly-Asp (RGD), which has been implicated as a recognition site in interactions between extracellular matrix (ECM) molecules and cell membrane receptors. RGD-containing synthetic peptides are known to inhibit attachment of endothelial cells to substrates, but their effect on angiogenesis has not been fully characterized. Aortic explants embedded in collagen gel in the absence of GRGDS generated branching microvessels through a process of endothelial migration and proliferation. Addition of GRGDS to the culture medium caused a marked inhibition of angiogenesis. In contrast, GRGES, a control peptide lacking the RGD sequence, failed to inhibit angiogenesis. The inhibitory effect of GRGDS was nontoxic and reversible. The angiogenic activity of aortic explants previously inhibited with GRGDS could be restored by incubating the cultures in GRGDS-free medium. These findings suggest that angiogenesis is an anchorage-dependent process that can be inhibited by interfering with the attachment of endothelial cells to the ECM. It also indicates that synthetic peptides can be used as probes to study the mechanisms by which the ECM regulates angiogenesis.

Amino Acid Sequence↗