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J M Isner

Publications and source records attributed to J M Isner.

At least 127 records · Page 7Linked to original sources
PubMed1997

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries.

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial-cell-specific mitogen; as such, its role in angiogenesis has been studied extensively. VEGF/VPF may also serve as a local, endogenous regulator of large-vessel endothelial cell integrity. Surprisingly, however, VEGF/VPF expression in normal and/or atherosclerotic vessels has not been previously characterized. Accordingly, we studied normal human arteries and veins as well as atherosclerotic and restenotic human coronary arteries for evidence of VEGF/VPF expression. VEGF/VPF was detected immunohistochemically in sections of normal human aorta, mammary artery, and saphenous vein. Moreover, VEGF/ VPF expression was identified in 32 (97%) of 33 pathological coronary arterial specimens; the extent of VEGF/VPF staining was graded as moderate to strong in 21 of the 32 (66%) positive specimens. VEGF/VPF double immunostaining and in situ hybridization demonstrated that smooth muscle cells constitute the principal cellular source of VEGF/VPF. VEGF/VPF immunostaining among primary atherosclerotic lesions localized predominantly to the extracellular matrix. In restenotic specimens, VEGF/VPF immunostaining was more prominently cellular, particularly among proliferating smooth muscle cells. Although VEGF/VPF expression was observed in areas of macrophage infiltration, double immunostaining failed to localize VEGF/VPF to macrophages in these foci; instead, double immunostaining clearly identified CD45RO-positive cells as responsible for VEGF/VPF expression in such areas. No correlation could be demonstrated between VEGF/VPF immunostaining and extent of vasa vasorum. These findings thus establish that postnatal VEGF/VPF expression is a feature of normal human arteries and veins and is often extensively expressed in arteries narrowed by atherosclerotic plaque. VEGF/VPF expression in the wall and/or plaque of medium to large vessels suggests a role for VEGF/VPF other than promoting angiogenesis. This role may involve maintenance and repair of luminal endothelium.

Aorta, Thoracic↗
PubMed1996

Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion.

BACKGROUND: Striated muscle has been shown to be capable of taking up and expressing foreign genes transferred in the form of naked plasmid DNA, although typically with a low level of gene expression. In the case of genes that encode secreted proteins, however, low transfection efficiency may not preclude bio-activity of the secreted gene product. Accordingly, we investigated the hypothesis that intramuscular (IM) gene therapy with naked plasmid DNA encoding vascular endothelial growth factor (VEGF) could augment collateral development and tissue perfusion in an animal model of hindlimb ischemia. METHODS AND RESULTS: Ten days after ischemia was induced in one rabbit hindlimb, 500 micrograms of phVEGF165, or the reporter gene LacZ, was injected IM into the ischemic hindlimb muscles. Thirty days later, angiographically recognizable collateral vessels and histologically identifiable capillaries were increased in VEGF transfectants compared with controls. This augmented vascularity improved perfusion to the ischemic limb, documented by a superior calf blood pressure ratio for phVEGF165 (0.85 +/- 0.05) versus controls (0.64 +/- 0.05, P < .01), improved blood flow in the ischemic limb (measured with an intra-arterial Doppler wire) at rest (phVEGF165 = 21.3 +/- 3.9 mL/min, control = 14.6 +/- 1.6 mL/min, P < .01) and after a vasodilator (phVEGF165 = 54.2 +/- 12.0 mL/min, control = 37.3 +/- 8.9 mL/min, P < .01) and increased microspheres in the adductor (phVEGF165 = 4.3 +/- 1.6 mL.min-1.100 g of tissue-1, control = 2.9 +/- 1.2 mL.min-1.100 g of tissue-1, P < .05) and gastrocnemius (phVEGF165 = 3.9 +/- 1.0 mL.min-1.100 g of tissue-1, control = 2.8 +/- 1.4 mL.min-1.100 g of tissue-1, P < .05) muscles of the ischemic limb. CONCLUSIONS: Ischemic skeletal muscle represents a promising target for gene therapy with naked plasmid DNA. IM transfection of genes encoding angiogenic cytokines, particularly those that are naturally secreted by intact cells, may constitute an alternative treatment strategy for patients with extensive peripheral vascular disease in whom the use of intravascular catheter-based gene transfer is compromised and/or prohibited.

Animals↗
PubMed1996

Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer.

BACKGROUND: Delinquent reendothelialization (rET) has been shown to have a permissive, if not facilitatory, impact on smooth muscle cell proliferation. This inverse relation has been attributed to certain functions of the endothelium, including barrier regulation of permeability, thrombogenicity, and leukocyte adherence, as well as production of growth-inhibitory molecules. Accordingly, the present investigation was designed to test the hypothesis that an endothelial cell (EC) mitogen could serve as the basis for a novel gene therapy strategy designed to facilitate EC regeneration, reduce neointimal thickening, and promote recovery of EC dysfunction after balloon injury. METHODS AND RESULTS: New Zealand White rabbits underwent simultaneous balloon injury and gene transfer of one femoral artery with phVEGF165, encoding the 165-amino acid isoform of vascular endothelial growth factor (VEGF), or pGSVLacZ. In each animal transfected with phVEGF165 or pGSVLacZ, the contralateral femoral artery was also subjected to balloon injury but not to gene transfer. For pGSVLacZ, rET remained incomplete at 4 weeks after transfection; in contrast, phVEGF165 produced prompt rET, which was 95% complete by 1 week. Furthermore, rET in the contralateral, balloon-injured, nontransfected limb of the VEGF group was similarly accelerated. Consequently, intimal thickening was diminished, thrombotic occlusion was less frequent, and recovery of EC-dependent vasomotor reactivity was accelerated in VEGF transfectants compared with control animals. A similar benefit was observed for the contralateral, balloon-injured, nontransfected limb. CONCLUSIONS: Catheter-mediated, site-specific arterial gene transfer of phVEGF165 can accelerate rET at local and remote sites, leading to inhibition of neointimal thickening, reduction in thrombogenicity, and restoration of endothelium-dependent vasomotor reactivity. These findings support the notion that gene transfer encoding for an EC-specific mitogen may be useful for preventing the complications, including restenosis, of balloon angioplasty.

Angioplasty, Balloon↗
PubMed1996

Therapeutic angiogenesis following arterial gene transfer of vascular endothelial growth factor in a rabbit model of hindlimb ischemia.

The plasmid phVEGF165, expressing the 165-amino-acid isoform of vascular endothelial growth factor (VEGF), an endothelial cell specific mitogen, was applied to the polymer coating of an angioplasty balloon and delivered percutaneously to the iliac artery of rabbits in which the femoral artery had been excised to cause hindlimb ischemia. Site-specific transfection of phVEGF165 resulted in augmented development of collateral vessels documented by serial angiograms, and increased capillary density as well as increased capillary/myocyte ratio documented histochemically at necropsy. Consequent amelioration of the hemodynamic deficit in the ischemic limb was documented by improvement in the calf blood pressure ratio (ischemic/normal limb) to 0.70 +/- 0.08 in the VEGF-transfected group vs 0.50 +/- 0.18 in controls (p < 0.05). These findings suggest that site-specific arterial gene transfer of VEGF165 may achieve physiologically meaningful therapeutic modulation of vascular insufficiency.

Animals↗
PubMed1996

Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb.

BACKGROUND: Preclinical findings suggest that intra-arterial gene transfer of a plasmid which encodes for vascular endothelial growth factor (VEGF) can improve blood supply to the ischaemic limb. We have used the method in a patient. METHODS: Our patient was the eighth in a dose-ranging series. She was aged 71 with an ischaemic right leg. We administered 2,000 micrograms human plasmid phVEGF165 that was applied to the hydrogel polymer coating of an angioplasty balloon. By inflating the balloon, plasmid DNA was transferred to the distal popliteal artery. FINDINGS: Digital subtraction angiography 4 weeks after gene therapy showed an increase in collateral vessels at the knee, mid-tibial, and ankle levels, which persisted at a 12-week view. Intra-arterial doppler-flow studies showed increased resting and maximum flows (by 82% and 72%, respectively). Three spider angiomas developed on the right foot/ankle about a week after gene transfer; one lesion was excised and revealed proliferative endothelium, the other two regressed. The patient developed oedema in her right leg, which was treated successfully. INTERPRETATION: Administration of endothelial cell mitogens promotes angiogenesis in patients with limb ischaemia.

Aged↗
PubMed1996

Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease.

The age-adjusted prevalence of peripheral arterial disease (PAD) in the U.S. population has been estimated to approach 12%. The clinical consequences of occlusive peripheral arterial disease (PAD) include pain on walking (claudication), pain at rest, and loss of tissue integrity in the distal limbs; the latter may ultimately lead to amputation of a portion of the lower extremity. Surgical bypass techniques and percutaneous catheter-based interventions may be used to successfully revascularize the limbs of certain patients with PAD. In many patients, however, the anatomic extent and distribution of arterial occlusion is too severe to permit relief of pain and/or healing of ischemic ulcers. No effective medical therapy is available for the treatment of such patients. The purpose of this clinical protocol is to document the safety of therapeutic angiogenesis achieved in this case by percutaneous catheter-based delivery of the gene encoding vascular endothelial growth factor (VEGF) in patients with PAD; and, as secondary objectives, investigate the bioactivity of this strategy to relieve rest pain and heal ischemic ulcers of the lower extremities. The rationale for this human protocol is based upon preclinical studies performed in a rabbit model of hindlimb ischemia. These studies are described in detail below and in the manuscripts enclosed in the Appendix to this proposal. In brief, a single intra-arterial bolus of VEGF recombinant human protein, delivered percutaneously to the ischemic limb via an intravascular catheter, resulted in angiographic, hemodynamic, physiologic, and histologic evidence of augmented collateral artery development. Subsequently, similar results were achieved using an angioplasty catheter with a hydrogel-coated balloon to deliver 400 micrograms of a plasmid containing the cDNA for VEGF to the internal iliac artery in the same animal model. Accordingly, we propose to administer arterial gene (VEGF) therapy to patients with rest pain and/or ischemic leg ulcers considered not to be candidates for conventional revascularization techniques. The dose of plasmid to be administered will be progressively escalated beginning with 500 micrograms for the first four patients, 1000 micrograms for the following six patients, 2000 micrograms for the third group of six patients, and 400 micrograms for the fourth group of six patients.

Arteries↗
PubMed1996

Distribution of hyaluronan during extracellular matrix remodeling in human restenotic arteries and balloon-injured rat carotid arteries.

BACKGROUND: The glycosaminoglycan hyaluronan (HA) is present in developing tissues and healing wounds and forms a loose, hydrated extracellular matrix (ECM) that promotes processes such as cell migration. To investigate the potential contribution of HA to the pathogenesis of restenosis, we studied (1) human lesions obtained by directional atherectomy and (2) experimentally induced neointima formation in balloon-injured rat carotid arteries. METHODS AND RESULTS: A biotinylated proteoglycan fragment that binds specifically to HA was used to stain atherectomy specimens from 29 human restenotic lesions (mean restenosis interval, 6.0+/-4.4 months) and 8 human primary lesions. The loose myxoid ECM typical of human restenotic arteries demonstrated intense, diffuse staining for HA. The intensity was inversely related to the density of immunostaining for collagen types I and III and was lowest in hypocellular primary atherosclerotic plaque. Among 24 rat carotid arteries retrieved 3, 7, 14, 28, 42, or 56 days after balloon injury and immunostained as well for proliferating cell nuclear antigen, staining for HA in the neointima reached a maximum 7 days after balloon injury and was associated with the presence of proliferating, PCNA-positive smooth muscle cells. CONCLUSIONS: Hyaluronan is a characteristic constituent of the loose myxoid ECM in human restenotic arteries and of the neointima in experimentally injured arteries. The presence of hyaluronan may be a marker for an initial phase of the extracellular matrix remodeling that occurs during the development of a fibroproliferative lesion and could facilitate biological processes such as cell migration.

Animals↗
PubMed1996

Processing of chimeric antisense oligonucleotides by human vascular smooth muscle cells and human atherosclerotic plaque. Implications for antisense therapy of restenosis after angioplasty.

BACKGROUND: Antisense oligonucleotides have been used in animals to inhibit the accumulation of vascular smooth muscle cells (VSMCs) after arterial injury. This has raised prospects for an oligonucleotide-mediated approach to prevent restenosis in patients undergoing angioplasty. However, little is known about the processing of oligonucleotides by human VSMCs or their bioavailability in human atherosclerotic tissue. METHODS AND RESULTS: Oligonucleotides were synthesized with a mixture of unmodified and sulfur-modified linkages (S-chimeric oligonucleotides). These were more stable than unmodified oligonucleotides and could be recovered from within human VSMCs after 36 hours. Oligonucleotide antisense to human proliferating cell nuclear antigen mRNA specifically reduced DNA synthesis (P < .01) and proliferating cell nuclear antigen protein content (P < .05) in human VSMCs. Confocal microscopy of both live and fixed cells showed modest oligonucleotide uptake that was primarily nuclear. Surprisingly, cationic liposomes did not enhance nuclear uptake but led to extensive, punctated cytoplasmic loading without an enhanced antisense effect. Oligonucleotides incubated with human coronary atherosclerosis fragments associated with cells within 1 hour, despite the presence of abundant extracellular matrix. CONCLUSIONS: S-chimeric oligonucleotides are stable and can specifically inhibit gene expression in human VSMCs. Nuclear transport is a feature of oligonucleotide processing by human VSMCs, indicating a potential influence at the nuclear level rather than with cytoplasmic mRNA. Cationic liposomes increased oligonucleotide uptake but not intracellular bioavailability, and S-chimeric oligonucleotides can be incorporated into cells within human atherosclerotic plaque, despite the presence of a dense extracellular matrix.

Angioplasty↗
PubMed1996

Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression.

Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF), an endothelial cell (EC)-specific mitogen, stimulates angiogenesis in vivo, particularly in ischemic regions. VEGF/VPF expression by cells of hypoxic tissues coincides with expression of its two receptors, KDR and flt-1, by ECs in the same tissues. We investigated whether hypoxia or hypoxia-dependent conditions operate in coordinating this phenomenon. Human umbilical vein and microvascular ECs were exposed to direct hypoxia or to medium conditioned (CM) by myoblasts maintained in hypoxia for 4 d. Control ECs were maintained in normoxia or normoxia-CM. Binding of 125I-VEGF to ECs was then evaluated. Hypoxic treatment of ECs had no effect on 125I-VEGF binding. However, treatment of ECs with hypoxia-CM produced a threefold increase in 125I-VEGF binding, with peak at 24 h (P < 0.001, ANOVA). Scatchard analysis disclosed that increased binding was due to a 13-fold increase in KDR receptors/cell, with no change in KDR affinity (Kd = 260 +/- 51 pM, normoxia-CM versus Kd = 281 +/- 94 pM, hypoxia-CM) and no change in EC number (35.6 +/- 5.9 x 10(3) ECs/cm2, normoxia-CM versus 33.5 +/- 5.5 x 10(3) ECs/cm2, hypoxia-CM). Similar results were obtained using CM from hypoxic smooth muscle cells. KDR upregulation was not prevented by addition to the hypoxia-CM of neutralizing antibodies against VEGF, tumor necrosis factor-alpha, transforming growth factor beta 1 or basic fibroblast growth factor. Similarly, addition of VEGF or lactic acid to the normoxia-CM had no effect on VEGF binding. We conclude that mechanism(s) initiated by hypoxia can induce KDR receptor upregulation in ECs. Hypoxic cells, normal or neoplastic, not only can produce VEGF/VPF, but can also modulate its effects via paracrine induction of VEGF/VPF receptors in ECs.

Animals↗
PubMed1996

Excimer laser angioplasty vs. balloon angioplasty in saphenous vein bypass grafts: quantitative angiographic comparison of matched lesions.

Technologies which ablate or debulk tissue may result in better angiographic outcomes by altering the elastic properties of the vessel wall. Accordingly, the procedural outcomes of 88 vein graft lesions treated by either excimer laser angioplasty with adjunct balloon angioplasty (PELCA + PTCA, n = 44) (Spectranetics CVX-300, 1.4-, 1.7-, or 2.0-MM catheters) or balloon angioplasty alone (PTCA, n = 44) were analyzed by quantitative angiography (Cardiac Measurement System). Lesions were individually matched for vessel position, reference diameter (RD), and minimal luminal diameter (MLD). Matching was deemed adequate as the preprocedure MLD (PELCA + PTCA, 1.14 +/- 0.48 mm; PTCA, 1.20 +/- 0.47 mm) and RD (PELCA + PTCA, 3.23 +/- 0.56 mm; PTCA, 3.25 +/- 0.57 mm) were not significantly different. There were also no significant differences between PELCA + PTCA- and PTCA-treated lesions with respect to patient age, graft age, lesion length, symmetry, and plaque area. Balloon diameter at maximal inflation was 2.77 +/- 0.55 mm (PELCA + PTCA group) and 2.84 +/- 0.59 mm (PTCA group), P = NS. Final MLD postprocedure was 2.17 +/- 0.54 mm and 2.19 +/- 0.55 mm for PELCA + PTCA- and PTCA-treated lesions (P = NS), respectively. Vessel stretch [(balloon diameter - MLD pre)/RD], elastic recoil [(balloon diameter - MLD post)/RD], and acute gain [(MLD post - MLD pre)/RD] were calculated and normalized for vessel size (RD). Vessel stretch (PELCA + PTCA, 0.60 +/- 0.22; PTCA, 0.59 +/- 0.24; P = NS), elastic recoil (PELCA + PTCA, 0.28 +/- 0.18; PTCA, 0.26 +/- 0.16), and acute gain (PELCA + PTCA, 0.34 +/- 0.24; PTCA, 0.31 +/- 0.23; P = NS) were not significantly different between the two treatment groups. In a matched population of successfully treated vein graft lesions, PELCA + PTCA did not reduce elastic recoil or improve immediate angiographic outcome, as compared with PTCA alone.

Adult↗
PubMed1996

The role of angiogenic cytokines in cardiovascular disease.

Angiogenic cytokines constitute a potentially novel form of therapy for patients with cardiovascular disease. The feasibility of using recombinant formulations of angiogenic growth factors to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia, "therapeutic angiogenesis", has now been well established. These studies have suggested that two angiogenic growth factors in particular, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), are sufficiently potent to merit further investigation. More recently, experiments performed in our laboratory have indicated that in the case of VEGF, a secreted protein, similar results may be achieved by percutaneous arterial gene transfer. Further laboratory and clinical studies may yield promising insights into the fundamental basis for native as well as therapeutic angiogenesis and at the same time more explicitly define the manner in which therapeutic angiogenesis may be successfully incorporated into clinical practice.

Animals↗
PubMed1996

VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts.

Several recent studies have demonstrated the potential for improving myocardial perfusion by the continuous administration of angiogenic growth factors. Studies in our laboratory have shown that a single intraarterial or intravenous bolus of the endothelial cell specific mitogen vascular endothelial growth factor (VEGF) can significantly improve perfusion in a rabbit ischemic limb model. To test the efficacy of this therapeutic approach in chronic myocardial ischemia, 18 Yorkshire pigs underwent a left thoracotomy followed by placement of an ameroid constrictor around the proximal circumflex coronary artery. Gradual occlusion of the artery (26 +/- 4 days) was accompanied by identifiable hypokinesis of the posterolateral wall of the left ventricle (2D echo). Thirty days postoperatively, rhVEGF(165) (2 mg; n = 8) or saline (n = 10) was administered directly into the left coronary ostium. Postadenosine myocardial perfusion studies using colored microspheres 30 days later demonstrated superior blood flow in the ischemic zone of the VEGF-treated hearts (ischemic/normal ratio 1.09 vs 0.97, P < 0.05) compared with those receiving saline injection. Four of eight VEGF-treated animals succumbed, however, to severe hypotension following VEGF administration. Therefore 500 micrograms of VEGF were administered intracoronary to five normal pigs. A significant drop in mean arterial pressure (-44.4 +/- 3.2%, P < 0.05 vs baseline) and peripheral resistance (-13.2 +/- 4.5%, P < 0.05 vs baseline) was accompanied by increased heart rate. IV administration of N(omega)-nitro-L-arginine (L-NNA), an EDRF inhibitor, restored blood pressure to baseline. We conclude that a single intracoronary bolus of VEGF is capable of significantly augmenting flow to collateral-dependent ischemic myocardium. The associated hypotension appears to be EDRF-mediated. Further studies are needed to define the best dose and route of administration of VEGF for the treatment of coronary insufficiency.

Adenosine↗
PubMed1996

A proliferation analysis of arterial neointimal hyperplasia: lessons for antiproliferative restenosis therapies.

Medial smooth muscle cell proliferation is frequently implicated as the major cause of coronary restenosis. Although antiproliferative agents have shown efficacy in animal studies, they are ineffective in human trials. To better understand these discrepancies, we performed a mathematical kinetic analysis of cellular proliferation in the neointimal hyperplasia of rats, pigs, and patients. A model was derived using a differential expression for proliferation, proportional to the number of cells present. Additional terms were included for inhibition of proliferation proportional to neointimal mass and time. The resulting equation was solved in closed form for the number of cells and proliferation rate. These equations were validated in the rat carotid artery injury model from published data. The model was then applied to the porcine coronary injury model, and then to clinical data obtained from angiographic human studies. Peak cellular proliferative activity in patients occurs at 16 days and continues at lower levels for much longer periods of time. Less than 10 generations of cells are sufficient to develop clinically significant restenosis. Conversely, proliferation rates in the two animal models (rats and pigs) are maximal at roughly 2 and 6 days, respectively, also continuing at low levels for extended time periods. Cell proliferation in restenosis is a highly controlled process, with comparatively few cell generations causing enough neointima for arterial obstruction to occur. Substantial cell kinetic differences occur across species. The rat exhibits high proliferation rates and rapid doubling times compared to patients and pigs, and is thus a highly 'proliferative' model. Such differences may be responsible for discrepant animal model and clinical trial results. These data may help determine the timing and strategy of therapy against clinical restenosis.

Animals↗
PubMed1996

Effect of subintimal resection on initial outcome and restenosis for native coronary lesions and saphenous vein graft disease treated by directional coronary atherectomy. A report from the CAVEAT I and II investigators. Coronary Angioplasty Versus Excisional Atherectomy Trial.

OBJECTIVES: This study was designed to determine whether the depth of tissue resection affected either immediate outcome or subsequent restenosis in patients treated by directional coronary atherectomy (DCA) in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) I and II studies. BACKGROUND: The relation between the depth of tissue resection, immediate outcome and subsequent restenosis in lesions treated with DCA has been controversial. METHODS: In CAVEAT I, 412 patients undergoing DCA had tissue samples available for analysis by the core laboratory, whereas in CAVEAT II, 113 patients had vein graft tissue specimens available. RESULTS: Subintimal deep arterial wall resection was demonstrated in 169 patients (41%) in CAVEAT I and 40 (35%) in CAVEAT II. The depth of tissue resection did not affect initial procedural outcome in either CAVEAT I or CAVEAT II, nor did it affect subsequent restenosis rates at 6 months in native coronary lesions (CAVEAT I, 50.8% for intimal resection vs. 51.2% for subintimal resection). In patients treated with vein graft disease (CAVEAT II), restenosis rates varied; when resection was limited to the intima, a restenosis rate of 40.4% was documented, whereas in patients with subintimal resection, the restenosis rate was 57.1%. This difference was not statistically significant (p = 0.144). CONCLUSIONS: This combined randomized series of DCA for treatment of primary native coronary artery and vein graft stenoses with quantitative coronary angiography and core laboratory pathologic assessment resolves the controversy created by previous experimental and clinical data regarding deep vessel wall resection and immediate and longer outcome. Directional atherectomy with deep arterial wall resection as practiced in these studies is safe and does not jeopardize initial success rates. More important, deep wall resection is not associated with significantly increased restenosis rates.

Atherectomy, Coronary↗
PubMed1996

Elevated levels of basic fibroblast growth factor in patients with limb ischemia.

Basic fibroblast growth factor (bFGF), a prototypic member of a family of heparin-binding growth factors, is angiogenic both in vitro and in vivo. Increased levels and activity of bFGF have been documented in a variety of diseases, including tumors. We sought to determine whether bFGF might be similarly elevated in patients with clinical evidence of limb ischemia. Serum was obtained at the time of percutaneous revascularization from patients with symptomatic peripheral vascular disease (46 procedures were performed on 40 patients). An enzyme-linked immunoassay specific for bFGF was used (limit of detection, 1 pg/ml; range in normal subjects, 0 to 5 pg/ml). Among the 40 patients (28 men, 12 women, mean age 70 years) studied, elevated circulating bFGF (> or = 10 pg/ml) was detected in 36 samples (78%); levels ranged from 10 to 310 pg/ml (mean +/- SEM = 62 +/- 12). In 16 (89%) of 18 patients with both rest pain and nonhealing ischemic ulcers, serum bFGF levels were elevated up to 30 times normal values. In conclusion, circulating levels of bFGF are elevated in patients with vascular insufficiency and may reflect a physiologic response to limb ischemia.

Aged↗
PubMed1996

Therapeutic angiogenesis: a new frontier for vascular therapy.

Angiogenic cytokines constitute a potentially novel form of therapy for patients with cardiovascular disease. The feasibility of using recombinant formulations of angiogenic growth factors to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia--'therapeutic angiogenesis'--has now been well established. These studies have suggested that two angiogenic growth factors in particular--basic fibroblast growth factor and vascular endothelial growth factor--are sufficiently potent to merit further investigation. More recently, experiments performed in our laboratory have indicated that, in the case of vascular endothelial growth factor--a secreted protein--similar results may be achieved by percutaneous arterial gene transfer. Further laboratory and clinical studies may yield promising insights into the fundamental basis for native as well as therapeutic angiogenesis, and at the same time more explicitly define the manner in which therapeutic angiogenesis may be successfully incorporated into clinical practice.

Animals↗