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Biomedical subjects

Michael Simons

Publications and source records attributed to Michael Simons.

At least 55 records · Page 3Linked to original sources
PubMed2003

Expression of VEGF and angiopoietins-1 and -2 during ischemia-induced coronary angiogenesis.

The mechanisms underlying coronary capillary growth in response to ischemia are undefined. We hypothesized that the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)/Tie-2 were involved in capillary growth as an adaptation to ischemia. To test this hypothesis we measured capillary density, and the expressions of VEGF, Ang-1, Ang-2, and the Tie-2 receptor and its phosphorylation state during repetitive episodes of myocardial ischemia in chronically instrumented canines. Repetitive episodes of ischemia were induced by multiple (once/hour; 8/day), brief (2 min) occlusions of the left anterior descending coronary artery for 1, 7, 14, or 21 days. A sham group received the same instrumentation as the experimental groups but not the occlusion protocol. Collateral blood flow (microspheres) progressively increased from 9 +/- 3 to 83 +/- 10 ml. min-1. 100 g-1 on day 21. Capillary density increased at day 7 from 2378 +/- 53 (sham) to 2962 +/- 60/mm2, but it decreased to 2594 +/- 39/mm2 at day 21. Both VEGF and Ang-2 expression in myocardial interstitial fluid (Western analyses) peaked at day 3 of the repetitive occlusions but waned thereafter. In contrast the expression of Ang-1 remained relatively constant at all times in the occlusion groups. In shams, the expression of VEGF and Ang-2 was low and constant at all times. Tie-2 phosphorylation myocardial decreased decreased at day 7 but increased at 21 days of occlusions (P < 0.05). Our results indicate that capillary density was augmented by myocardial ischemia, but after development of collaterals and restoration of flow to the ischemic zone, capillary density returned to control levels. The change in capillary density paralleled with VEGF and Ang-2 expression but was inversely related to Tie-2 phosphorylation. We speculate the coronary angiogenesis is a coordinated event involving the expression of both VEGF and Ang-2 and that therapeutic angiogenic strategies may ultimately require treatment with more than a single factor.

Angiogenesis Inducing Agents↗
PubMed2003

Syndecan-4 modulates basic fibroblast growth factor 2 signaling in vivo.

Syndecan-4 is one of the principal heparan sulfate-carrying proteins on the cell surface. Unlike other members of syndecan family, syndecan-4 mediates phosphatidylinositol 4,5-bisphosphate 2 (PIP(2))-dependent PKC-alpha activation, and overexpression of syndecan-4 in vitro results in enhanced FGF2 signaling. The present study was designed to test the functional effect of increased syndecan-4 expression in endothelial cells in transgenic mice. Several transgenic mice lines expressing syndecan-4 cDNA under control of human endothelial nitric oxide (NO) synthase (eNOS) promoter were generated. Exogenous syndecan-4 was mainly expressed in the heart, brain, and lungs. In particular, the heart demonstrated the greatest increase in the ratio of transgenic-to-native syndecan-4 gene expression. Vessels from the eNOS-syndecan-4 mice demonstrated more pronounced vasodilation to FGF2 but not to VEGF-A(165), sodium nitroprusside, and A 23187 compared with wild-type mice. To elucidate the mechanism of this effect, we measured NO release from primary cardiac endothelial cells isolated from transgenic or wild-type adult mice. Cells from the eNOS-syndecan-4 transgenic mice had a significant increase in FGF2- and VEGF-A(165)-induced NO release compared with endothelial cells from the wild-type mice. However, the absolute magnitude of this increase was higher for FGF2 than VEGF-A(165). In conclusion, enhanced syndecan-4 expression in mouse cardiac endothelial cells results in preferential augmentation of FGF2 but not VEGF-A(165)-induced NO release.

Animals↗
PubMed2003

Endothelial progenitor cells: precursors for angiogenesis.

The presence of endothelial progenitor cells has been demonstrated in the bone marrow and systemic circulation of adults, thus raising the possibility of a novel strategy to induce therapeutic angiogenesis for ischemic arterial disease. Successful incorporation into sites of actively occurring angiogenesis in numerous animal models has accelerated the enthusiasm for exploiting their therapeutic capacity in humans and has led to the recent use of putative endothelial precursor cells in phase I feasibility and safety studies. However, key biological issues remain ill defined. The relative contribution of these cells to postnatal physiological and pathological neovascularization has not been fully characterized. Furthermore, the molecular phenotype of the putative endothelial progenitor cell and the processes leading to their mobilization from the bone marrow and homing to sites of angiogenesis have yet to be elucidated. This review addresses these fundamental issues that warrant further basic investigation before the full therapeutic potential of these cells can be achieved within appropriate target patients.

Adult↗
PubMed2003

Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease.

The aim of therapeutic angiogenesis in cardiovascular disease states is to improve myocardial and peripheral extremity perfusion and function within ischemic regions that are not amenable to traditional modes of revascularization. Substantial "proof of concept," efficacy, and safety data have emerged from numerous animal models and clinical trials that fibroblast growth factor (FGF), when administered by various delivery strategies, has a therapeutic angiogenic capacity. This initial excitement has been replaced by cautious optimism in the wake of results from larger, randomized, double-blinded placebo-controlled trials of both FGF gene and protein administration. A greater understanding of the profound placebo effect, careful patient selection, and improved endpoint assessment are factors that need to be addressed in this rapidly evolving era of molecular therapeutics.

Animals↗
PubMed2003

Arteriogenesis: lessons learned from clinical trials.

Arteriogenesis is a naturally occurring process leading to formation of the true bypass collaterals capable of providing normal blood flow to the distal vascular bed. Promoting the development of such conductance blood vessels appears to be the most attractive therapeutic strategy in occlusive atherosclerotic disease. Although our understanding of molecular events regulating the blood vessel formation in adult organs is far from complete, there is a body of knowledge that allowed for planning and conduction of the early phase I and II clinical trials of therapeutic angiogenesis. Substantial human safety data, as well as important considerations of the growth factor formulation, delivery and duration of action have emerged from these trials. The current review focuses on lessons learned from double-blind, randomized Phase II trials of arteriogenesis.

Adult↗
PubMed2003

Translational physiology: porcine models of human coronary artery disease: implications for preclinical trials of therapeutic angiogenesis.

"Therapeutic angiogenesis" describes an emerging field of cardiovascular medicine whereby new blood vessels are induced to grow to supply oxygen and nutrients to ischemic cardiac or skeletal muscle. Various methods of producing therapeutic angiogenesis have been employed, including mechanical means, gene therapy, and the use of growth factors, among others. The use of appropriate large-animal models is essential if these therapies are to be critically evaluated in a preclinical setting before their use in humans, yet little has been written comparing the various available models. Over the past decade, swine have been increasingly used in studies of chronic ischemia because of their numerous similarities to humans, including minimal preexisting coronary collaterals as well as similar coronary anatomy and physiology. Consequently, this review describes the most commonly used swine models of chronic myocardial ischemia with special attention to regional myocardial blood flow and function and critically evaluates the strengths and weaknesses of each model in terms of utility for preclinical trials of angiogenic therapies.

Angina Pectoris↗
PubMed2002

Fibroblast growth factor-specific modulation of cellular response by syndecan-4.

Proteoglycans participate in growth factor interaction with the cell surface through their heparan sulfate chains (HS), but it is not known if they are otherwise involved in growth factor signaling. It appears now that the syndecan-4 core protein, a transmembrane proteoglycan shown previously to bind phosphatidylinositol 4,5-bisphosphate (PIP(2)) and activate PKC alpha, participates in mediating the effects of fibroblast growth factor (FGF)2 on cell function. Mutations in the cytoplasmic tail of syndecan-4 that either reduced its affinity to PIP(2) (PIP(2)(-)) or disrupted its postsynaptic density 95, disk large, zona occludens-1 (PDZ)-dependent binding (PDZ(-)) produced a FGF2-specific dominant negative phenotype in endothelial cells as evidenced by the marked decline of their migration and proliferation rates and the impairment of their capacity to form tubes. In both cases, the molecular mechanism was determined to consist of a decrease in the syndecan-4-dependent activation of PKC alpha. This decrease was caused either by inhibition of FGF2-induced syndecan-4 dephosphorylation in the case of the PDZ(-) mutation or by disruption of basolateral targeting of syndecan-4 and its associated PDZ-dependent complex in the case of the PIP(2)(-) mutation. These results suggest that PKCalpha activation and PDZ-mediated formation of a serine/threonine phosphatase-containing complex by syndecan-4 are downstream events of FGF2 signaling.

Animals↗
PubMed2002

Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites.

Binding of basic fibroblast growth factor (FGF2) to its high affinity receptors requires the presence of specific heparan sulfate (HS) moieties on the cell surface that act as coreceptors. To determine the contribution of cell-surface HS to modulation of FGF2-dependent cell growth, we studied the changes in the cell mass and FGF2 binding of endothelial cell HS under normoxic and hypoxic conditions in vitro. Both large vein and cardiac microvascular endothelial cells cultured under hypoxic conditions demonstrated an increase in the ratio of cell-surface HS to chondroitin sulfate (CS), as well as an increase in the number of low affinity (HS-associated) binding sites for FGF2 with no change in the apparent K(d). This increase in the number of HS-FGF2 binding sites, in the absence of a significant change in FGF receptor expression, resulted in enhanced responsiveness of hypoxic, compared with normoxic, endothelial cells to FGF2 stimulation. Gene expression studies demonstrated increased expression of the key regulatory enzyme responsible for HS chain synthesis, 1,4 GlcNAc transferase (GlcNAcT-I), as well as increased expression of 2-O sulfotransferase (HS2ST), the enzyme responsible for sulfation of IdoA, a crucial part of the HS-FGF2 binding site. Transduction of cells with an adenovirus encoding a HIF-1alpha expression construct resulted in a similar increase in GlcNAcT-I and HS2ST expression. We conclude that hypoxia increases endothelial cell responsiveness to FGF2 by promoting preferential synthesis of HS rather than CS chains and increasing the number of FGF2-binding sites on HS chains. Both of these events are mediated by a HIF-1alpha-dependent increase in expression of the enzymes GlnNAcT-I and HS2ST. This shift in cell-surface HS composition results in enhanced cell sensitivity to FGF2-induced growth stimulation.

Animals↗
PubMed2002

Protein kinase C (PKC) delta regulates PKCalpha activity in a Syndecan-4-dependent manner.

The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant. Syndecan-4/PIP(2)-dependent PKCalpha activity was significantly increased in PKCdelta DN cells, while PKCdelta overexpression was accompanied by decreased PKCalpha activity. PKCdelta-overexpressing cells exhibited a significantly lower proliferation rate and an impaired tube formation in response to FGF2, which were mirrored by similar observations in PKCalpha DN endothelial cells. These findings suggest that PKCdelta is the kinase responsible for syndecan-4 phosphorylation, which, in turn, attenuates the cellular response to FGF2 by reducing PKCalpha activity. The reduced PKCalpha activity then leads to impaired endothelial cell function. We conclude that PKCdelta regulates PKCalpha activity in a syndecan-4-dependent manner.

Amino Acid Sequence↗
PubMed2002

Clustering induces redistribution of syndecan-4 core protein into raft membrane domains.

Syndecan-4 is a heparan sulfate-carrying core protein that has been directly implicated in fibroblast growth factor 2 (FGF2) signaling. Recent studies have suggested that many signaling proteins localize to the raft compartment of the plasma cell membrane. To establish whether syndecan-4 is present in the raft compartment, we have studied the distribution of the core protein and an Fc receptor (FcR)-syndecan-4 chimera prior to and following clustering with FGF2 or antibodies. Whereas unclustered syndecan-4 was present predominantly in the non-raft membrane compartment, clustering induced extensive syndecan-4 redistribution to the rafts as demonstrated by the sucrose gradient centrifugation and life confocal microscopy. Although syndecan-4 and caveolin-1 moved in tandem, syndecan-4 was not present in caveolae, a major subset of raft compartments. We conclude that syndecan-4 clustering induces its redistribution to the non-caveolae raft compartment. This process may play an important role in syndecan-4-mediation of FGF2 signaling.

Animals↗
PubMed2002

Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice.

Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD.

Age of Onset↗
PubMed2002

Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial.

BACKGROUND: Single-bolus intracoronary administration of fibroblast growth factor-2 (FGF2) improved symptoms and myocardial function in a phase I, open-label trial in patients with coronary artery disease. We conducted the FGF Initiating RevaScularization Trial (FIRST) to evaluate further the efficacy and safety of recombinant FGF2 (rFGF2). METHODS AND RESULTS: FIRST is a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 microg/kg (n=337 patients). Efficacy was evaluated at 90 and 180 days by exercise tolerance test, myocardial nuclear perfusion imaging, Seattle Angina Questionnaire, and Short-Form 36 questionnaire. Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. rFGF2 reduced angina symptoms as measured by the angina frequency score of the Seattle Angina Questionnaire (overall P=0.035) and the physical component summary scale of the Short-Form 36 (pairwise P=0.033, all FGF groups versus placebo). These differences were more pronounced in highly symptomatic patients (baseline angina frequency score < or =40 or Canadian Cardiovascular Society score of III or IV). None of the differences were significant at 180 days because of continued improvement in the placebo group. Adverse events were similar across all groups, except for hypotension, which occurred with higher frequency in the 30-microg/kg rFGF2 group. CONCLUSIONS: A single intracoronary infusion of rFGF2 does not improve exercise tolerance or myocardial perfusion but does show trends toward symptomatic improvement at 90 (but not 180) days.

Adult↗
PubMed2002

Magnetic resonance imaging demonstrates improved regional systolic wall motion and thickening and myocardial perfusion of myocardial territories treated by laser myocardial revascularization.

OBJECTIVES: This study was designed to investigate the use of magnetic resonance (MR) functional and perfusion imaging to evaluate laser myocardial revascularization (LMR). BACKGROUND: Most clinical studies of LMR have shown improvements in angina class and exercise capacity, with minimal or absent improvements in myocardial perfusion and function. METHODS: Fifteen patients who underwent percutaneous Biosense-guided holmium:yttrium aluminum garnet LMR to areas of viable but ischemic myocardium were followed clinically and underwent functional and perfusion MRI at baseline, 30 days and 6 months. RESULTS: The mean age was 64 +/- 11 years; four patients were women. The ejection fraction was 47.4 +/- 14.0%. Angina class at baseline was 3.4 +/- 0.6 and improved to 2.5 +/- 1.4 at six months (p = 0.054). Exercise time at baseline was 298 +/- 97 s and increased to 350 +/- 95 s at 30 days and 365 +/- 79 s at six months, p = 0.04. There were no significant changes in nuclear perfusion scans. Although MR determined that resting radial motion and thickening of the target wall were significantly less than normal at baseline (p < 0.001), they improved significantly during follow-up (wall thickening: baseline, 30.6 +/- 11.7%; day 30, 41.2 +/- 13.3% and day 180, 44.2 +/- 11.9%, p = 0.01). The size of the underperfused myocardial area was 14.5 +/- 5.4% at baseline and was reduced to 6.3 +/- 2.8% at 30 days and 7.7 +/- 3.7% at 6 months (p < 0.001). CONCLUSIONS: This small phase I, open-label, uncontrolled study of MR functional and perfusion imaging in patients undergoing Biosense-guided LMR suggests a beneficial effect of this treatment strategy on myocardial function and perfusion. The efficacy of Biosense-guided LMR is being evaluated in a large phase II, randomized, blinded placebo-controlled trial with an MRI substudy (DIRECT).

Adult↗
PubMed2002

The effect of intracoronary fibroblast growth factor-2 on restenosis after primary angioplasty or stent placement in a pig model of atherosclerosis.

BACKGROUND: Therapeutic angiogenesis, if combined with primary percutaneous transluminal coronary angioplasty or stent placement, could improve the outcome of patients suffering from multifocal coronary disease. HYPOTHESIS: Because of the concern that angiogenic growth factors might promote restenosis, we studied the effect of a single intracoronary administration of recombinant fibroblast growth factor (rFGF)-2 on restenosis after balloon angioplasty and stent placement in a pig model of coronary atherosclerosis. METHODS: In 24 Yucatan minipigs, coronary lesions were induced by arterial injury and 3 months of atherogenic diet. After 3 months, repeat catheterization was performed with balloon dilation or stent placement at the injured sites, with a follow-up of 6 weeks. Results were monitored using quantitative angiography, intravascular ultrasound (IVUS), and histomorphometry. RESULTS: Intracoronary rFGF-2 2 microg/kg did not affect neointima formation or remodeling in this model. A small but significant aggravation of late lumen loss was observed in the reference segments of the rFGF-2-treated group. Angiographic and echographic late lumen loss, intimal hyperplasia, and arterial remodeling, as well as histologic neointima were all similar in the rFGF-2- and the vehicle-treated group. Confirming earlier studies from our group and those of others, stented arteries compared with balloon-dilated arteries had increased angiographic late lumen loss, a trend toward increased intimal hyperplasia and decreased remodeling. CONCLUSION: We conclude that rFGF-2 does not aggravate restenosis after balloon dilation or stenting in this pig model of coronary atherosclerosis. Future combinations of angioplasty and therapeutic angiogenesis in a single session should be pursued as a feasible and safe strategy.

Angioplasty, Balloon, Coronary↗
PubMed2002

Modulation of microvascular signaling by heparan sulfate matrix: studies in syndecan-4 transgenic mice.

The onset of tissue ischemia is associated with significant changes in the expression of heparan sulfate- (HS) carrying core proteins that, in turn, lead to alterations in composition of the extracellular HS matrix. Since HS can bind numerous growth factors and cytokines, such changes in the HS matrix content can have profound effects on the ability of these factors to interact with their target cells. To investigate the role of increased HS matrix content on microvascular function, we used alpha-myosin heavy chain (MHC) promoter to overexpress a HS-carrying core protein, syndecan-4, in cardiac myocytes in mice. Mice expressing the transgene (alpha MHC-S4) demonstrated a significant increase in nitric oxide (NO) release in the coronary effluent in response to fibroblast growth factor 2 (FGF2, 1 microg/mL) administration despite similar expression levels of NO synthase genes II and III (iNOS and eNOS, respectively). In vitro studies of coronary microvessels derived from alpha MHC-S4 mice demonstrated increased relaxation response to FGF2 compared to control mice. At the same time, vasodilator response to adenosine diphosphate (ADP) was significantly impaired in alpha MHC-S4 mice-derived microvessels. Addition of exogenous HS to microvessels derived from control mice enhanced FGF2-induced vasodilation while inhibiting ADP-induced vasomotion. The vasomotor activity of the endothelial receptor-independent agent (A23187) and the endothelium-independent agent (sodium nitroprusside) was not affected by heparan sulfate. These results demonstrate that alterations in HS production have a profound and heterogeneous effect on endothelial receptor-dependent vasodilators and point to a novel role of the HS matrix in regulation of microvascular homeostasis.

Adenosine Diphosphate↗
PubMed2002

Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein.

OBJECTIVE: The long-term effects of surgical fibroblast growth factor 2 therapy are examined. METHODS: In a randomized, double-blind study, fibroblast growth factor 2 (10 microg or 100 microg) or placebo (n = 8 each) was delivered in the ungraftable myocardial territory of patients concomitantly undergoing coronary artery bypass grafting. Patients were followed up to 32.2 +/- 6.8 months postoperatively with clinical assessment and nuclear perfusion imaging. RESULTS: Baseline patient characteristics were similar between the 3 groups. There were 2 late deaths, one of pancreatic cancer and one of undetermined cause (both in the 100-microg fibroblast growth factor 2 group). Two patients (both in the control group) underwent a total of 6 repeat cardiac catheterizations for recurrent coronary events. Mean Canadian Cardiovascular Society angina class improved at late follow-up from baseline in all groups (P < or = .02); however, patients treated with either dose of fibroblast growth factor 2 had significantly more freedom from angina recurrence than those treated with placebo (P =.03). Late nuclear perfusion scans revealed a persistent reversible or a new, fixed perfusion defect in the ungraftable territory of 4 of 5 patients who received placebo versus only 1 of 9 patients treated with fibroblast growth factor 2 (P =.02). The overall sum of left ventricular stress perfusion defect scores was also lower in fibroblast growth factor 2-treated patients than in control subjects (1.3 +/- 1.4 vs 3.9 +/- 2.1, respectively; P =.04). A trend toward a higher late left ventricular ejection fraction was noted in fibroblast growth factor 2-treated patients (55.1% +/- 14.6% vs 44.3% +/- 6.5%, fibroblast growth factor 2-treated patients versus control subjects; P =.12). CONCLUSIONS: These data suggest that surgical angiogenic therapy with sustained-release fibroblast growth factor 2 may result in a prolonged myocardial revascularization effect that could translate into clinical benefit.

Coronary Artery Bypass↗
PubMed2002

Medical imaging techniques in the evaluation of strategies for therapeutic angiogenesis.

Recent advancements in our understanding of the basic biology of angiogenesis have prompted a focus on practical applications, both in cardiovascular disease and in oncology. The focus on practical applications has stimulated development of novel noninvasive tools that provide serial assessment of ongoing vessel growth in vivo. Nuclear imaging (SPECT, PET) and x-ray angiography have been used to assess changes in perfusion and anatomic appearance, respectively, after induced neovascular development. New MRI techniques provide the ability to identify early changes in vivo that are more sensitive to detection of the effects of new vessel growth than x-ray angiography or nuclear imaging. These new MRI techniques include measurement of blood delivery to the myocardium, development of intramyocardial vasculature, and incremental changes in regional myocardial contractile function. With the combination of methods now available, we expect to be able to track key steps of angiogenesis in vivo and to assess the efficacy of angiogenic therapies. These new imaging capabilities offer crucial information which we hope will hasten the identification and deployment of effective pharmaceutical therapies as an adjunct or alternative to invasive treatments of ischemic disease by targeted stimulation of angiogenesis, and of cancer, by targeted inhibition of angiogenesis.

Animals↗