Vascular Endothelial Growth Factor (VEGF165) Plus Basic Fibroblast Growth Factor (bFGF) Producing Cells induce a Mature and Stable Vascular Network—a Future Therapy for Ischemically Challenged Tissue (original) (raw)
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Laboratory Investigation, 2000
Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is an angiogenic cytokine with potential for the treatment of tissue ischemia. To investigate the properties of the new blood vessels induced by VPF/VEGF, we injected an adenoviral vector engineered to express murine VPF/VEGF 164 into several normal tissues of adult nude mice or rats. A dose-dependent angiogenic response was induced in all tissues studied but was more intense and persisted longer (months) in skin and fat than in heart or skeletal muscle (Յ3 weeks). The initial response (within 18 hours) was identical in all tissues studied and was characterized by microvascular hyperpermeability, edema, deposition of an extravascular fibrin gel, and the formation of enlarged, thin-walled pericyte-poor vessels ("mother" vessels). Mother vessels developed from preexisting microvessels after pericyte detachment and basement membrane degradation. Mother vessels were transient structures that evolved variably in different tissues into smaller daughter vessels, disorganized vessel tangles (glomeruloid bodies), and medium-sized muscular arteries and veins. Vascular structures closely resembling mother vessels and each mother vessel derivative have been observed in benign and malignant tumors, in other examples of pathological and physiological angiogenesis, and in vascular malformations. Together these data suggest that VPF/VEGF has a role in the pathogenesis of these entities. They also indicate that the angiogenic response induced by VPF/VEGF is heterogeneous and tissue specific. Finally, the muscular vessels that developed from mother vessels in skin and perimuscle fat have the structure of collaterals and could be useful clinically in the relief of tissue ischemia. (Lab Invest 2000, 80:99-115).
The Regulation of Blood Vessel Growth by Vascular Endothelial Growth Factor
Annals of the New York Academy of Sciences, 1995
A fundamental property of vascular endothelial cells is the ability to proliferate and form a network of capillaries.'.2 This process is known as "angiogenesis" and requires at least three steps: i) degradation of the extracellular matrix of a local venule, ii) chemotaxis of endothelial cells toward an angiogenic stimulus, and iii) proliferation of endothelial cells. Angiogenesis is prominent during embryonic development and somatic growth but in a normal adult it only takes place following injury or, in a cyclical fashion, in the endometrium and in the ovary.'%2 Angiogenesis plays a significant role in the pathogenesis of a variety of disorders including cancer, proliferative retinopathies, rheumatoid arthritis or psoriasis. Therefore, inhibition of angiogenesis may constitute an attractive strategy for the treatment of such disorders. Conversely, disorders characterized by inadequate tissue perfusion such as obstructive atherosclerosis and diabetes are expected to benefit from agents able to promote endothelial cell growth and angiogenesis. A variety of factors have been identified as potential positive regulators of angiogenesis: aFGF, bFGF, EGF, TGF-a, TGF-P, PGE2, monobutyrin, TNF-a, PD-ECGF, angiogenin and interleukin-8.'~~ This article will review a recently identified family of directly-acting endothelial cell mitogens and angiogenic factors known as vascular endothelial growth factor (VEGF) or vascular permeability factor (VPF).3,4 These factors are products of the same gene and, by alternative exon splicing, may exist in four different iso-form^.^-^ Recent studies point to VEGF as a major regulator of physiological and pathological angiogenesis. Furthermore, the angiogenic activity of VEGF appears to be sufficient to achieve therapeutic benefit in animal models of coronary or limb ischemia. Biological Properties of VEGF A unique aspect of VEGF is its target all specificity.' VEGF is a potent mitogen (ED5o 2-10 pM) for vascular endothelial cells, but it is apparently devoid of mitogenic activity for other cell types.'-" VEGF is also able to induce a marked angiogenic response in the chick chorioallantoic membrane.'O-I2 VEGF also proa Corresponding author.
Timing and Targeting of Cell-Based VEGF165 Gene Expression in Ischemic Tissue
Journal of Surgical Research, 2009
Background. Therapeutic angiogenesis has become a key technology in experimental and clinical medicine. Only few data are available on the effects of timing and targeting of therapeutic proteins after cellbased gene transfer. This work investigates such effects after temporary expression of vascular endothelial growth factor 165 (VEGF 165 ), the most commonly used angiogenic protein for therapeutic purposes.
Vascular Endothelial Growth Factor andde NovoMammalian Angiogenesis
Microvascular Research, 1996
The time course and potency of the de novo angiogenic response to vascular endothelial growth factor isoform 165 (VEGF 165 ) at approximate physiologic doses was assessed using the nonsurgical mesenteric-window angiogenesis assay in adult rats. Daily i.p. injections of VEGF 165 at 4.8, 48, and 480 pM were given for Days 0-4, controls receiving the vehicle. Groups of 10 animals per treatment group were sacrificed on Days 7, 14, and 21. Using microscopic morphometry and image analysis, the vascularized area, a measure of microvascular spatial extension, and the microvascular length, a measure of microvascular density, were measured. At 4.8 and 480 pM, VEGF 165 induced significant angiogenesis as early as on Day 7, suggesting a direct angiogenic effect. This very rapid angiogenic response to VEGF 165 is distinct from other angiogenesis reactions, including angiogenesis induced by basic fibroblast growth factor, studied using the same methodology. During the early angiogenic phase, the increase in microvascular spatial expansion dominated over the increase in microvascular density. The specific response to VEGF 165 peaked on Day 7 for the 4.8 pM dose and on Day 14 for the 480 pM dose, which was the more potent. It is, moreover, noteworthy that no statistically significant response was induced by the intermediate dose of VEGF 165 (48 pM) at any observation time. The data thus suggest that, although VEGF 165 at near physiologic doses apparently acts as a direct angiogen, its dose-related effect in terms of angiogenesis is nonlinear. ᭧
Angiogenic Responses of Vascular Endothelial Growth Factors in Periadventitial Tissue
Human Gene Therapy, 2003
Recent discovery of new members of the vascular endothelial growth factor (VEGF) family has generated much interest as to which members may be best suited for therapeutic angiogenesis in various tissues. In this study we evaluated angiogenic responses of the different members of the VEGF family in vivo using adenoviral gene transfer. Adenoviruses (1 3 10 9 plaque-forming units [pfu]) encoding for VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-C DNDC and VEGF-D DNDC (DNDC are proteolytically cleaved forms) were transferred locally to the periadventitial space of the rabbit carotid arteries using a collar technique that allows efficient local transfection of the periadventitial tissue. Expression of the transfected VEGFs was confirmed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Seven days after the gene transfer maximum neovessel formation was observed in VEGF-A-, VEGF-D-, and VEGF-D DNDC-transfected arteries. VEGF-C DNDC also showed angiogenic activity whereas VEGF-B was not effective in inducing angiogenesis. Pericytes were detected around the neovessels, which also frequently showed the presence of intraluminal erythrocytes. Infiltration of inflammatory cells in response to VEGF-D and VEGF-D DNDC was less prominent than that caused by other VEGFs. In line with the absence of lymphatics in the normal carotid arteries no significant evidence of lymphatic vessel formation was seen in response to any of the studied VEGFs in the periadventitial space. The results help to define possibilities for local angiogenic therapy around blood vessels and support the concept that angiogenic effects may be tissue-specific and depend both on the growth factor ligands and the target tissues. It is concluded that VEGF-A, VEGF-D, and VEGF-D DNDC are the best candidates for therapeutic angiogenesis when delivered around large arteries.
The American journal of pathology, 1998
Neovascularization of ischemic muscle may be sufficient to preserve tissue integrity and/or function and may thus be considered to be therapeutic. The regulatory role of vascular endothelial growth factor (VEGF) in therapeutic angiogenesis was suggested by experiments in which exogenously administered VEGF was shown to augment collateral blood flow in animals and patients with experimentally induced hindlimb or myocardial ischemia. To address the possible contribution of postnatal endogenous VEGF expression to collateral vessel development in ischemia tissues, we developed a mouse model of hindlimb ischemia. The femoral artery of one hindlimb was ligated and excised. Laser Doppler perfusion imaging (LDPI) was employed to document the consequent reduction in hindlimb blood flow, which typically persisted for up to 7 days. Serial in vivo examinations by LDPI disclosed that hindlimb blood flow was progressively augmented over the course of 14 days, ultimately reaching a plateau between...
Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia
The FASEB Journal, 2006
The critical role of vascular endothelial growth factor (VEGF) expression levels in developmental angiogenesis is well established. Nonetheless, the effects of different local (microenvironmental) VEGF concentrations in ischemia have not been studied in the adult organism, and VEGF delivery to patients has been disappointing. Here, we demonstrate the existence of both lower and upper threshold levels of microenvironmental VEGF concentrations for the induction of therapeutic vessel growth in ischemia. In the ischemic hind limb, implantation of myoblasts transduced to express VEGF 164 at different levels per cell increased blood flow only moderately, and vascular leakage and aberrant preangiomatous vessels were always induced. When the same total dose was uniformly distributed by implanting a monoclonal population derived from a single VEGF-expressing myoblast, blood flow was fully restored to nonischemic levels, collateral growth was induced, and ischemic damage was prevented. Hemangiomas were avoided and only normal, pericyte-covered vessels were induced persisting over 15 mo. Surprisingly, clones uniformly expressing either lower or higher VEGF levels failed to provide any functional benefit. A biphasic effect of VEGF dose on vessel number and diameter was found. Blood flow was only improved if vessels were increased both in size and in number. Microenvironmental VEGF concentrations determine efficacy and safety in a therapeutic setting.-Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia. FASEB J. 20, E2277-E2287 (2006)