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PubMed2005

Expression profiling reveals functionally important genes and coordinately regulated signaling pathway genes during in vitro angiogenesis.

Angiogenesis is a complex multicellular process requiring the orchestration of many events including migration, alignment, proliferation, lumen formation, remodeling, and maturation. Such complexity indicates that not only individual genes but also entire signaling pathways will be crucial in angiogenesis. To define an angiogenic blueprint of regulated genes, we utilized our well-characterized three-dimensional collagen gel model of in vitro angiogenesis, in which the majority of cells synchronously progress through defined morphological stages culminating in the formation of capillary tubes. We developed a comprehensive three-tiered approach using microarray analysis, which allowed us to identify genes known to be involved in angiogenesis and genes hitherto unlinked to angiogenesis as well as novel genes and has proven especially useful for genes where the magnitude of change is small. Of interest is the ability to recognize complete signaling pathways that are regulated and genes clustering into ontological groups implicating the functional importance of particular processes. We have shown that consecutive members of the mitogen-activated protein kinase and leukemia inhibitory factor signaling pathways are altered at the mRNA level during in vitro angiogenesis. Thus, at least for the mitogen-activated protein kinase pathway, mRNA changes as well as the phosphorylation changes of these gene products may be important in the control of blood vessel morphogenesis. Furthermore, in this study, we demonstrated the power of virtual Northern blot analysis, as an alternative to quantitative RT-PCR, for measuring the magnitudes of differential gene expression.

Bayes Theorem↗
PubMed2004

Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth.

We evaluated the significance of the host kallikrein-kinin system in tumor angiogenesis and tumor growth using two rodent models genetically deficient in a kallikrein-kinin system. Inoculation of Walker 256 carcinoma cells into the s.c. tissues of the back of normal Brown Norway Kitasato rats (BN-Ki rats) resulted in the rapid development of solid tumors with marked angiogenesis. By contrast, in kininogen-deficient Brown Norway Katholiek rats (BN-Ka rats), which cannot generate intrinsic bradykinin (BK), the weights of the tumors and the extent of angiogenesis were significantly less than those in BN-Ki rats. Daily administration of B(2) receptor antagonists significantly reduced angiogenesis and tumor weights in BN-Ki rats to levels similar to those in BN-Ka rats but did not do so in BN-Ka rats. Angiogenesis and tumor growth were significantly suppressed in B(2) receptor knockout mice bearing sarcoma 180 compared with their wild-type counterparts. Immunoreactive vascular endothelial growth factor (VEGF) was localized in Walker tumor stroma more extensively in BN-Ki rats than in BN-Ka rats, although immunoreactive B(2) receptor also was detected in the stroma to the same extent in both types of rats. Cultured stromal fibroblasts isolated from BN-Ki rats and BN-Ka rats produced VEGF in response to BK (10(-8)-10(-6) m), and this stimulatory effect of BK was abolished with a B(2) receptor antagonist, Hoe140 (10(-5) m). These results suggest that BK generated from kininogens supplied from the host may facilitate tumor-associated angiogenesis and tumor growth by stimulating stromal B(2) signaling to up-regulate VEGF production mainly in fibroblasts.

Animals↗
PubMed2004

Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer.

Angiogenesis is essential for both primary and metastatic tumor growth. Tumor blood vessel formation is complex and regulated by many factors. Ovarian carcinomas have a poor prognosis, often associated with multifocal intraperitoneal dissemination accompanied by intense neovascularization. To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites of patients with untreated ovarian carcinoma. We observed high numbers of plasmacytoid dendritic cells (PDCs) and significant stromal-derived factor (CXCL-12/SDF)-1 in their malignant ascites, attracting PDCs into the tumor environment. We now show that tumor-associated PDCs induced angiogenesis in vivo through production of tumor necrosis factor alpha and interleukin 8. By contrast, myeloid dendritic cells (MDCs) were absent from malignant ascites. MDCs derived in vitro suppressed angiogenesis in vivo through production of interleukin 12. Thus, the tumor may attract PDCs to augment angiogenesis while excluding MDCs to prevent angiogenesis inhibition, demonstrating a novel mechanism for modulating tumor neovascularization. Because dendritic cells (DCs) have long been known to affect tumor immunity, our data also implicate DCs in regulation of tumor neoangiogenesis, suggesting a novel role of DCs in tumor pathology.

Animals↗
PubMed2004

Ablation of peripheral dopaminergic nerves stimulates malignant tumor growth by inducing vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis.

Many important physiological and pathological processes are modulated by angiogenesis. It has been shown that initiation of this angiogenic process is an essential early step in the progression of malignant tumors. We report here that ablation of peripheral dopaminergic nerves markedly increased angiogenesis, microvessel density, microvascular permeability, and growth of malignant tumors in mice. Endogenous peripheral dopamine acted through D2 receptors as significantly more angiogenesis and tumor growth was observed in D2 dopamine receptor knockout mice in comparison with controls. The vascular endothelial growth factor receptor 2 phosphorylation, which is critical for promoting angiogenesis, was also significantly more in tumor endothelial cells collected from the dopamine-depleted and D2 dopamine receptor knockout animals. These results reveal that peripheral endogenous neurotransmitter dopamine might be an important physiological regulator of vascular endothelial growth factor-mediated tumor angiogenesis and growth and suggest a novel link between endogenous dopamine, angiogenesis, and tumor growth.

Animals↗
PubMed2006

Fibulins 3 and 5 antagonize tumor angiogenesis in vivo.

Lethal tumor growth and progression cannot occur without angiogenesis, which facilitates cancer cell proliferation, survival, and dissemination. Fibulins (FBLN) 5 and 3 are widely expressed extracellular matrix proteins that regulate cell proliferation in a context-specific manner. Reduced FBLN-5 expression has been associated with cancer formation and progression in humans, whereas its constitutive expression antagonizes endothelial cell angiogenic sprouting in vitro. Thus, FBLN-5 may suppress tumorigenesis by preventing tumor angiogenesis. FBLN-3 is homologous to FBLN-5 and expressed in endothelial cells, yet its role in tumorigenesis and angiogenesis is unknown. We find FBLN-3 expression to be altered in some human tumors and that its constitutive expression in endothelial cells inhibited their proliferation, invasion, and angiogenic sprouting, as well as their response to vascular endothelial growth factor as measured by p38 mitogen-activated protein kinase activation. In endothelial cells, both FBLNs (a) reduced angiogenic sprouting stimulated by basic fibroblast growth factor (bFGF); (b) inhibited matrix metalloproteinase expression and activity; and (c) stimulated tissue inhibitor of metalloproteinase expression. More importantly, both FBLNs prevented angiogenesis and vessel infiltration into bFGF-supplemented Matrigel plugs implanted in genetically normal mice, as well as decreased the growth and blood vessel density in tumors produced by MCA102 fibrosarcoma cells implanted s.c. into syngeneic mice. Our findings establish FBLN-3 and FBLN-5 as novel angiostatic agents capable of reducing tumor angiogenesis and, consequently, tumor growth in vivo and suggest that these angiostatic activities may one day be exploited to combat tumor angiogenesis and metastasis in cancer patients.

Amino Acid Sequence↗
PubMed2005

Headpin: a serpin with endogenous and exogenous suppression of angiogenesis.

Headpin is a novel serine proteinase inhibitor (serpin) with constitutive mRNA expression in histologically normal oral mucosa but with lost or down-regulated expression in head and neck squamous cell carcinoma. Several serpin family members are similarly lost in multiple cancer types and hold tumor suppressor functions including the inhibition of angiogenesis. However, the functional significance for the loss of headpin expression in cancer is not known. Using immunohistochemical analysis of invasive squamous cell carcinoma and matched normal squamous mucosa of patient specimens, headpin expression was lost or down-regulated in the vast majority of tumor specimens. We investigated the functions of exogenous recombinant headpin and endogenously expressed headpin related to angiogenesis. In a rat corneal assay of neovascularization, recombinant headpin protein blocked in vivo angiogenesis mediated by interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF). In assays of cellular events in angiogenesis, headpin blocked the invasion, migration, and tube formation of endothelial cells. In light of our findings of nuclear subcellular localization of headpin, we investigated the expression and secretion of angiogenic factors and found reduced mRNA, protein, and promoter activities of IL-8 and VEGF. Finally, using a murine flank tumor model, headpin expression reduced growth and microvessel density in tumors derived from headpin-expressing UMSCC1 cells relative to those from vector control cells. These findings of nuclear regulatory functions of a serpin in the inhibition of angiogenesis bring new understanding to the cellular and molecular mechanisms of serpins. Therefore, this novel serpin targets diverse mechanisms against tumor angiogenesis on which to base therapeutic strategies.

Animals↗
PubMed2006

Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis.

The mechanism of thrombin-induced angiogenesis is poorly understood. Using a gene chip array to investigate the pro-malignant phenotype of thrombin-stimulated cells, we observed that thrombin markedly up-regulates growth-regulated oncogene-alpha (GRO-alpha) in several tumor cell lines as well as endothelial cells by mRNA and protein analysis. Thrombin enhanced the secretion of GRO-alpha from tumor cells 25- to 64-fold. GRO-alpha is a CXC chemokine with tumor-associated angiogenic as well as oncogenic activation following ligation of its CXCR2 receptor. GRO-alpha enhanced angiogenesis in the chick chorioallantoic membrane assay 2.2-fold, providing direct evidence for GRO-alpha as an angiogenic growth factor. Anti-GRO-alpha antibody completely inhibited the 2.7-fold thrombin-induced up-regulation of angiogenesis, as well as the 1.5-fold thrombin-induced up-regulation of both endothelial cell cord formation in Matrigel and growth in vitro. Thrombin as well as its PAR-1 receptor activation peptide [thrombin receptor activation peptide (TRAP)] as well as GRO-alpha all markedly increased vascular regulatory proteins and growth factors: matrix metalloproteinase (MMP)-1, MMP-2, vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), CD31, and receptors KDR and CXCR2 in human umbilical vein endothelial cells. All of the thrombin/TRAP gene up-regulations were completely inhibited by anti-GRO-alpha antibody and unaffected by irrelevant antibody. Similar inhibition of gene up-regulation as well as thrombin-induced chemotaxis was noted with small interfering RNA (shRNA) GRO-alpha KD 4T1 breast tumor and B16F10 melanoma cells. In vivo tumor growth studies in wild-type mice with shRNA GRO-alpha KD cells revealed 2- to 4-fold impaired tumor growth, metastasis, and angiogenesis, which was not affected by endogenous thrombin. Thus, thrombin-induced angiogenesis requires the up-regulation of GRO-alpha. Thrombin up-regulation of GRO-alpha in tumor cells as well as endothelial cells contributes to tumor angiogenesis.

Amino Acid Sequence↗
PubMedDate not supplied

Basic-fibroblast-growth-factor-mediated de novo angiogenesis is more effectively suppressed by low-molecular-weight than by high-molecular-weight heparin.

We recently reported that the subcutaneous (s.c.) administration of a low-molecular-weight heparin (LMWH) fraction significantly inhibited de novo angiogenesis in the mesentery induced by the intraperitoneal (i.p.) injection of saline to adult rats compared with unfractionated heparin and high-molecular-weight heparin (HMWH) fractions. The present study assesses the effect on basic fibroblast growth factor (bFGF)-mediated de novo angiogenesis in the mesentery of the systemic administration of a LMWH fraction (2.6 kD) and a series of four HMWH fractions (about 20 kD) with varying degrees of polydispersity, charge density and anticoagulant activity. bFGF, a prototypic heparin-binding angiogenic growth factor, was injected i.p. at 220 pM on days 0-4. The heparins were given s.c. on days 0-13 or 0-14 at doses which were approximately within the range used clinically. Angiogenesis was assessed by microscopic morphometry and image analysis in groups of animals killed on days 14 and 15. Compared with the saline control, the LMWH and three of the HMWHs significantly inhibited angiogenesis in terms of microvascular length (MVL), a measure of microvascular density. Interestingly, the vascularized area (VA), a measure of microvascular spatial extension, and the total microvascular length (VA x MVL) were significantly lower in the LMWH-treated animals than in the animals treated with one of the HMWHs. The total microvascular length was, moreover, significantly reduced in the LMWH-treated animals compared with the combined data of all the HMWH-treated animals. No significant effects were related to the degree of charge density and anticoagulant activity of the heparins. In view of the putative significant angiogenic role of bFGF in human angiogenesis diseases, the present findings may have implications for the choice of anticoagulant treatment modality for patients suffering from cancer and other angiogenesis diseases.

Animals↗
PubMedDate not supplied

Effect of basic fibroblast growth factor on angiogenesis and growth of isografted bone: quantitative in vitro-in vivo analysis in mice.

Basic fibroblast growth factor (bFGF), a constituent of bone and cartilage matrix, has been shown to be a potent mitogen for osteoblasts and chondrocytes and yet an inhibitor of chondrocyte terminal differentiation in cell culture. To characterize the effect of bFGF on bone formation, whole neonatal murine femora were cultured in the presence or absence of bFGF and a neutralizing antibody against bFGF. In vitro, femoral elongation was provided by cartilage growth only; the calcified diaphyseal zone stained by oxytetracycline did not increase. When bFGF was added to the culture medium, longitudinal growth of the proximal and distal cartilage was inhibited in a dose-dependent manner (p < 0.05), and the number of hypertrophic chondrocytes in the growth plate was reduced. This phenomenon was absent in the presence of a neutralizing antibody, which when given alone significantly promoted femoral elongation. In contrast, in vivo after transplantation into adult mice bearing dorsal skin fold chambers, femora rapidly calcified after revascularization. This observation supports the notion that bone formation largely depends on angiogenesis-mediated events. To verify this hypothesis, angiogenesis and bone formation were quantified using bFGF known to be a stimulator of angiogenesis. Calcification of grafted femora was accelerated by bFGF given intraperitoneally. The neutralizing antibody slightly suppressed angiogenesis and femoral elongation (not statistically significant), whereas intravenous injections of both substances did not reveal a significant modulatory effect. In vivo the effect of systemically administered bFGF was inhomogeneous, but there was a strong correlation between angiogenesis and endochondral calcification (p < 0.001). These results suggest that exogenous bFGF modulates bone formation in vitro by inhibition of terminal differentiation of chondrocytes in the growth plate, and angiogenesis and concomitant in vivo events are pivotal in the promotion of rapid bone formation.

Animals↗
PubMed1990

Selective inhibition by magnosalin and magnoshinin, compounds from 'shin-i' (Flos magnoliae), of adjuvant-induced angiogenesis and granuloma formation in the mouse pouch.

Inhibitory effects of magnosalin and magnoshinin, compounds from the crude drug 'Shin-i' (Flos magnoliae), on angiogenesis and pouch granuloma formation induced by an adjuvant containing croton oil were investigated. Magnosalin inhibited angiogenesis 2.4-fold (intra-pouch) and 9.7-fold (intraperitoneal) more strongly than granuloma formation. The inhibition of angiogenesis by magnosalin was 5-fold (intra-pouch) and 21-fold (intraperitoneal) weaker than that by hydrocortisone. In contrast, intraperitoneal magnoshinin inhibited granuloma formation 2.5-fold more strongly than angiogenesis. The regression coefficients of anti-angiogenesis vs. the inhibition of granuloma formation were 1.79 for magnosalin, 1.11 for hydrocortisone, and 0.61 for magnoshinin. These results show that the anti-chronic inflammatory effect of 'Shin-i' was caused by selective inhibition of angiogenesis by magnosalin and of granuloma formation by magnoshinin.

Adjuvants, Immunologic↗
PubMed2002

Regulation of endothelial cell survival and apoptosis during angiogenesis.

The process of angiogenesis plays an important role in many physiological and pathological conditions. Inhibition of endothelial cell (EC) apoptosis providing EC survival is thought to be an essential mechanism during angiogenesis. Many of the angiogenic growth factors inhibit EC apoptosis. In addition, the adhesion of ECs to the extracellular matrix or intercellular adhesion promotes EC survival. In contrast, increasing evidence suggests that the induction of EC apoptosis may counteract angiogenesis. In this review, we focus on the regulation of EC survival and apoptosis during angiogenesis and especially on the effects and intracellular signaling promoted by angiogenic growth factors, endogenous angiogenic inhibitors (such as angiostatin, endostatin, and thrombospondin-1), and the adhesion to the extracellular matrix. Furthermore, we discuss the effects of cross talk between adhesion molecules and growth factors. Understanding the molecular mechanisms involved in the regulation of EC survival and apoptosis may provide new targets for the development of new therapies to enhance angiogenesis in the case of tissue-ischemia (eg, the neovascularization of myocardium) or to inhibit angiogenesis in the case of neovascularization-dependent disease (eg, tumor, diabetic retinopathy).

Animals↗
PubMed2002

Divergence of angiogenic and vascular permeability signaling by VEGF: inhibition of protein kinase C suppresses VEGF-induced angiogenesis, but promotes VEGF-induced, NO-dependent vascular permeability.

Vascular endothelial growth factor (VEGF) promotes angiogenesis by a variety of mechanisms including stimulation of endothelial cell proliferation and migration and increasing vascular permeability. Although its mitogenic activity is mediated primarily by the beta(2)-isoforms of protein kinase C (PKC), little is known about the signaling pathways transducing its other physiological properties. Accordingly, we used a novel inhibitor molecule to examine the role of PKC isoforms alpha and beta in mediating VEGF-induced angiogenesis and vascular permeability. Because conventional inhibitors of PKC, such as staurosporine or calphostin C, also inhibit a variety of other protein kinases, we used a novel compound to specifically inhibit PKC. A myristoylated peptide, which mimics the pseudosubstrate motif of PKC-alpha and -beta subtypes, has been shown to be a highly selective and cell-permeable inhibitor of PKC. Blocking led, as expected, to abrogation of VEGF-induced endothelial cell proliferation in vitro. In vivo, VEGF-induced angiogenesis was impaired by myristoylated peptide. Surprisingly, selective inhibition of PKC induced vascular permeability in vivo via a NO-dependent mechanism. Moreover, PKC inhibition led to a 6.4-fold induction of NO synthase (NOS) activity in endothelial cells. Our findings demonstrate that activation of PKC is a major signaling pathway required for VEGF-induced proliferation and angiogenesis, whereas vascular permeability was enhanced by blocking PKC. Inhibition of calcium-dependent PKC by itself led to induction of NOS. Although NOS is a downstream target for VEGF-induced angiogenesis, its induction by PKC inhibition was not sufficient to promote neovascularization. These results reveal that angiogenesis and vascular permeability induced by VEGF are mediated by mechanisms which ultimately diverge.

Animals↗
PubMed2006

Transcriptional regulators of angiogenesis.

Angiogenesis, the process by which new blood vessels develop from a pre-existing vascular network, is essential for normal development and in certain physiological states. Inadequate or excessive angiogenesis has been incriminated in a number of pathologic states. For example, vaso-occlusive disease arising from atherosclerosis can lead to ischemia, a situation in which enhanced angiogenesis would be beneficial. Conversely, overzealous angiogenesis can contribute to tumor development and in this case inhibition of angiogenesis is desirable. Thus, strategies to induce or inhibit angiogenesis are of considerable therapeutic interest.

Animals↗
PubMed2000

Hyperhomocysteinemia impairs angiogenesis in response to hindlimb ischemia.

Hyperhomocysteinemia (HH) is an independent risk factor for atherosclerosis, including peripheral arterial occlusive disease (PAOD). Because angiogenesis and collateral vessel formation are important self-salvage mechanisms for ischemic PAOD, we examined whether HH modulates angiogenesis in vivo in a rat model of hindlimb ischemia. Rats were divided into 3 groups: the control group was given tap water, the HH group was given water containing L-methionine (1 g x kg(-1) x d(-1)), and the HH+L-arg group was given water containing methionine (1 g x kg(-1) x d(-1)) and l-arginine (2.25 vol%). At day 14 of the dietary modifications, the left femoral artery and vein were excised, and the extent of angiogenesis and collateral vessels in the ischemic limb were examined for 4 weeks. Plasma homocysteine levels significantly increased (P:<0.001), and plasma and tissue contents of nitrite+nitrate as well as tissue cGMP levels significantly decreased in the HH group compared with the control group (P:<0.01). Laser Doppler blood flowmetry (LDBF) revealed a significant decrease in the ischemic/normal limb LDBF ratio in the HH group at days 7, 14, 21, and 28 (P:<0.01 versus control). Angiography revealed a significant decrease in the angiographic score in the HH group at day 14 (P:<0.001 versus control). Immunohistochemistry of ischemic tissue sections showed a significant reduction in the capillary density in the HH group (P:<0. 001 versus control). Oral l-arginine supplementation in rats with HH (HH+L-arg) restored the decreased plasma and tissue nitrite+nitrate and cGMP contents (P:<0.05) as well as angiogenesis, as assessed by LDBF (P:<0.05 versus HH), angiographic score (P:<0.01 versus HH), and capillary density (P:<0.001 versus HH). In summary, HH impaired ischemia-induced angiogenesis and collateral vessel formation in a rat model of hindlimb ischemia in vivo. The mechanism of the HH-induced impairment of angiogenesis might be mediated in part by a reduced bioactivity of endogenous NO in the HH state.

Angiography↗
PubMed2003

Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1.

BACKGROUND: Although hepatocyte growth factor (HGF) is an angiogenic growth factor, it is still unclear how it exerts its angiogenic effects. Thus, we focused on the role of an essential transcription factor for angiogenesis, ets-1. In this study, we addressed the following specific questions: (1) what genes responsible for angiogenesis can be regulated by HGF and (2) whether upregulation of gene expression for angiogenesis is dependent on ets-1. METHODS AND RESULTS: In human endothelial cells, HGF significantly stimulated the matrix-degrading pathway, such as the production of matrix metalloprotease-1 (MMP-1) through its specific receptor, c-met. In addition, HGF also significantly increased HGF itself and its specific receptor, c-met. Moreover, HGF significantly increased the transcription activity and mRNA expression of ets-1 in a time-dependent manner. Importantly, transfection of antisense ets-1 oligodeoxynucleotides (ODN) resulted in a significant reduction in MMP-1, HGF and c-met. Interestingly, HGF also stimulated ets-1 mRNA in vascular smooth muscle cells, similar to endothelial cells. Of importance, transfection of antisense ets-1 ODN resulted in a significant decrease in vascular endothelial growth factor (VEGF) and HGF expression, whereas HGF stimulated both HGF and VEGF expression. Moreover, in vivo transfection of ets-1 antisense ODN resulted in an inhibition of angiogenesis induced by the HGF gene in a rat ischemic hindlimb model. CONCLUSIONS: Here, we demonstrated that HGF stimulated the expression of MMP-1, VEGF, HGF itself, and c-met in human endothelial cells and vascular smooth muscle cells. Upregulation of angiogenesis-related genes was largely dependent on the induction of ets, especially ets-1. These data provide new information about the mechanisms of angiogenesis.

Animals↗
PubMed1999

Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo.

BACKGROUND: Endothelial cells (ECs) represent the critical cellular element responsible for postnatal angiogenesis. Because ACE inhibitors may favorably affect endothelial function, we investigated the hypothesis that administration of the ACE inhibitor quinaprilat could enhance angiogenesis in vivo. METHODS AND RESULTS: Ten days after resection of 1 femoral artery, New Zealand White (NZW) rabbits were randomly assigned to receive recombinant human vascular endothelial growth factor (rhVEGF) administered as a single intra-arterial injection (n=6), quinaprilat (n=8) or captopril (n=7) administered as a daily subcutaneous injection, or no treatment (controls, n=6). Angiogenesis was monitored in vivo by measurement of blood pressure, vasoreactivity, and resistance in ischemic versus normal limbs at day 10 (D10) and D40; angiographic studies to identify sites of neovascularization were performed at D10 and D40, and morphometric analysis of capillary density in the ischemic limb was performed at necropsy (D40). Both functional and morphological outcomes documented augmented angiogenesis in quinaprilat-treated rabbits similar to that observed for rhVEGF and superior to that observed with either captopril or no drug (controls). Residual ACE activity was equivalent for the captopril and quinaprilat groups in plasma (42.54+/-0.03% versus 41.53+/-0.02%, P=NS) but not in tissue, where quinaprilat lowered ACE activity significantly (P<0.01) compared with captopril (13% versus 61%). CONCLUSIONS: ACE inhibition with quinaprilat promotes angiogenesis in a rabbit model of hindlimb ischemia. Thus, nonsulfhydryl ACE inhibitors with high tissue affinity may be potentially useful for therapeutic angiogenesis in ischemic tissues. Moreover, previous evidence that ACE inhibition benefits patients with myocardial ischemia may be due in part to augmented collateral development.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis.

Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell proliferation and migration, primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). Reactive oxygen species (ROS) derived from NAD(P)H oxidase are critically important in many aspects of vascular cell regulation, and both the small GTPase Rac1 and gp91(phox) are critical components of the endothelial NAD(P)H oxidase complex. A role of NAD(P)H oxidase in VEGF-induced angiogenesis, however, has not been defined. In the present study, electron spin resonance spectroscopy is utilized to demonstrate that VEGF stimulates O2*- production, which is inhibited by the NAD(P)H oxidase inhibitor, diphenylene iodonium, as well as by overexpression of dominant-negative Rac1 (N17Rac1) and transfection of gp91(phox) antisense oligonucleotides in human umbilical vein endothelial cells (ECs). Antioxidants, including N-acetylcysteine (NAC), various NAD(P)H oxidase inhibitors, and N17Rac1 significantly attenuate not only VEGF-induced KDR tyrosine phosphorylation but also proliferation and migration of ECs. Importantly, these effects of VEGF are dramatically inhibited in cells transfected with gp91(phox) antisense oligonucleotides. By contrast, ROS are not involved in mediating these effects of sphingosine 1-phosphate (S1P) on ECs. Sponge implant assays demonstrate that VEGF-, but not S1P-, induced angiogenesis is significantly reduced in wild-type mice treated with NAC and in gp91(phox-/-) mice, suggesting that ROS derived from gp91(phox)-containing NAD(P)H oxidase play an important role in angiogenesis in vivo. These studies indicate that VEGF-induced endothelial cell signaling and angiogenesis is tightly controlled by the reduction/oxidation environment at the level of VEGF receptor and provide novel insights into the NAD(P)H oxidase as a potential therapeutic target for angiogenesis-dependent diseases.

Animals↗
PubMed2004

Angiogenesis with biomaterial-based drug- and cell-delivery systems.

Angiogenesis, the formation of new blood vessels from existing ones, is an important event in several biological processes, including wound healing. It plays a key role in determining the final functionality and integration of any implanted medical device. In addition, angiogenesis is a required event for organ development and has been accepted as a rate-limiting step in engineering tissue replacements. Besides these regenerative processes, uncontrolled angiogenesis is also involved in a number of pathologies, including tumor growth and metastases. Like angiogenesis, biomaterials also play a role in wound healing after medical device implantation and in tissue engineering. Interactions between the device biomaterials and host tissue will factor into the final device integration. Additionally, tissue-engineering strategies utilize biomaterials to a great extent because the paradigm of tissue engineering involves the use of cells, growth factors and scaffolding matrices in order to regenerate or replace tissue. Since almost all tissues are three-dimensional, the biomaterial scaffold plays an integral role in the paradigm. This review will emphasize the influence of biomaterials on angiogenesis as it applies to medical device implantation, tissue engineering and therapies for pathological angiogenesis.

Animals↗