Abnormal Blood Vessel Growth Research Articles

Kaposi's Sarcoma and HIV-Tat: Challenges to Antiangiogenesis Research

Kaposi's sarcoma (KS) is characterized by an abnormal growth of blood vessels. KS was found mainly in older men of Mediterranean or African origin (classic KS) or in patients after organ transplantation (iatrogenic KS). However, in the early 1980s, an aggressive epidemic form, linked to AIDS, was noticed and was one of the first clues to the existence of HIV-1 pandemy. The link between KS occurrence and HIV has raised multiple hypotheses. The drastic reduction of KS after the introduction of HAART, suggests HIV as a powerful co-factor for KS progression. We and others have contributed to the elucidation of KS cell nature and the possible involvement of extracellular HIV Tat. Tat is proangiogenic and is a true promoter of KS lesions acting as a VEGFR2 ligand both on KS and endothelial cells, in addition Tat is able to bind and activate chemokine receptors on monocytes and granulocytes causing a pro-inflammatory status. Evaluation of the effects of extracellular Tat on KS cells by microarray analysis after 24 h of incubation shows an interesting clustering of gene products involved in signal transduction, especially GTP-ase, Kinase and cAMP activity, confirming that Tat acts extracellularly by ways that are probably unrelated to its nuclear activity. KS occurrence is reduced by HAART but still present and in Africa is one of the most frequent oncologic disease. To find suitable drugs with low toxic impact on KS patients, we have tested several drugs and gene therapy approaches in in vivo models. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Mast cells and eosinophils: A novel link between inflammation and angiogenesis in allergic diseases

Mast cells and eosinophils are the key cells in the early and late stages of allergic inflammation. There is increasing evidence that angiogenesis plays an important role both in the development of inflammation and in the pathophysiology of tissue remodeling during allergic disorders. In this review we provide recent data showing a link between allergy and angiogenesis and some possible mechanisms through which vascular endothelial growth factor and the immune system can interact. We discuss the multifaceted roles of mast cells and eosinophils in tissue remodeling and angiogenesis during allergic diseases and whether these cells can be both source and target cells for pro-angiogenic mediators.

The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease

Vascular endothelial growth factors (VEGFs) are a family of polypeptides with a highly conserved structure. In mammals, VEGFs have roles in vascular development, development of lymphatic vessels and disease-related angiogenesis.The existence of VEGF-like molecules and their receptors in simple invertebrates without a vascular system indicates that this family of growth factors emerged at a very early stage in the evolution of multicellular organisms to mediate primordial developmental functions.

Visible light exposure induces VEGF gene expression through activation of retinoic acid receptor-α in retinoblastoma Y79 cells

Neovascularization of the retina and choroids is the pathological hallmark of many retinopathies, but its molecular mechanisms remain unclear. Vascular endothelial growth factor (VEGF), which is induced by hypoxia or cytokines, plays a critical role in the abnormal growth of blood vessels. In this study, we report that visible light exposure induces VEGF gene expression in retinoblastoma Y79 cells. Fluorescent light exposure (700 lux, wavelength 400 approximately 740 nm) caused a significant increase in VEGF transcripts and protein levels. Such an induction seemed to be specific to certain cells, including photoreceptor cells, because light-induced VEGF expression was not observed in either nontransformed cells, such as retinal pigment epithelium cells, and bovine aortic endothelial cells or transformed cells, such as CV-1 and HepG2 cells. Pertussis toxin and guanosine 5'-[beta-thio]diphosphate, specific inhibitors for rhodopsin-associated G protein, blunted this induction. Progressive deletion and site-specific mutation analyses indicate that light stimulation increases VEGF promoter activity through G+C-rich sequence, which is proven by Sp1 binding sites by supershift assays. Electrophoretic mobility shift assays show that light stimulation increases Sp1 binding. Synthetic retinoic acid receptor-alpha (RARalpha) antagonist completely abrogated light-mediated increase in VEGF expression. Transfection of Y79 cells with dominant negative mutant of RARalpha significantly attenuated the light-mediated induction of VEGF promoter activity. In conclusion, our data indicate that light exposure increases VEGF expression through the mechanisms involving activation of Sp1 and RARalpha signaling in Y79 cells. This study provides new insight into the role of visible light in the transcription and induction of VEGF gene expression.

56. Intraplacental Gene Transfer of IGF-1 Corrects Intrauterine Growth Restriction in the Rabbit Model

The growth of abnormal blood vessels in the eye, associated with proliferative diabetic retinopathy, retinopathy of prematurity and wet age-related macular degeneration (AMD), is the major cause of blindness in developed countries. Current treatments that destroy or inhibit the growth of existing blood vessels can delay vision loss but do not affect the underlying disease and neovascularization is a recurring problem. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic and neuroprotective protein that is naturally produced in the eye. When delivered to the eye via an adenovirus vector, PEDF can block growth of new blood vessels and trigger the regression of established abnormal vessels in animal models for AMD and diabetic retinopathy.

Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.

The existence of factors that stimulate blood vessel growth, thereby recruiting a neovascular supply to nourish a growing tumour, was postulated many decades ago, although the identification and isolation of these factors proved elusive. Now, vascular endothelial growth factor (VEGF), which was identified in the 1980s, is recognized as an essential regulator of normal and abnormal blood vessel growth. In 1993, it was shown that a monoclonal antibody that targeted VEGF results in a dramatic suppression of tumour growth in vivo, which led to the development of bevacizumab (Avastin; Genentech), a humanized variant of this anti-VEGF antibody, as an anticancer agent. The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blocking angiogenesis is an effective strategy to treat human cancer.

Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis.

Use of long-term constitutive expression of VEGF for therapeutic angiogenesis may be limited by the growth of abnormal blood vessels and hemangiomas. We investigated the relationship between VEGF dosage and the morphology and function of newly formed blood vessels by implanting retrovirally transduced myoblasts that constitutively express VEGF164 into muscles of adult mice. Reducing VEGF dosage by decreasing the total number of VEGF myoblasts implanted did not prevent vascular abnormalities. However, when clonal populations of myoblasts homogeneously expressing different levels of VEGF were implanted, a threshold between normal and aberrant angiogenesis was found. Clonal myoblasts that expressed low to medium levels of VEGF induced growth of stable, pericyte-coated capillaries of uniform size that were not leaky and became VEGF independent, as shown by treatment with the potent VEGF blocker VEGF-TrapR1R2. In contrast, clones that expressed high levels of VEGF induced hemangiomas. Remarkably, when different clonal populations were mixed, even a small proportion of cells with high production of VEGF was sufficient to cause hemangioma growth. These results show for the first time to our knowledge that the key determinant of whether VEGF-induced angiogenesis is normal or aberrant is the microenvironmental amount of growth factor secreted, rather than the overall dose. Long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal angiogenesis without other exogenous growth factors.

Screening for retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a rare condition that affects the immature blood vessels in the retina, the inner lining of the inner wall of the eye. During development, the retinal blood vessels grow from the back of the eye outwards towards the edges. Beginning at 22 days post conception (Roberts 1985) it is destined to occur in the ‘warm, stable and hypoxic environment of amniotic fluid’ (Flynn 1992, p161). In a term baby this process is completed a few weeks before delivery, but in babies born prematurely the process is incomplete. It was not until the introduction of the binocular indirect ophthalmoscope that advances occurred (Petersen et al 1994). By allowing examination of the peripheral as well as the posterior area of the retina, earlier studies were repeated. Retinopathy of prematurity was identified as arising from the permanent constriction and necrosis of some of the vessels while other vessels attempted to revascularise the retina (Gardner and Hagedorn 1990). The condition was identified as common, occurring more frequently in infants of low birth weight (McCormick 1977). It results in retinal scar formation, retinal traction and detachment, leading to visual impairment and blindness. Since then many studies have been undertaken in the search to identify ‘etiological relationships between conditions and/or treatments of premature infants and ROP severity’ (Phelps 1992, p350). A comprehensive review of the medical and nursing journals over a ten-year period, complemented by literature obtained from professional ophthalmic organisations, suggests that, globally, ROP has provided a roller coaster ride of highs and lows since its discovery. The ill effects of disturbances to the uterine environment were first recognised by Terry in 1942, who described ‘an abnormal growth of fibroplastic tissue and blood vessels behind the lens, causing bilateral blindness in premature infants’ (Petersen et al 1994, p2799). Retinopathy of prematurity, then known as Retrolental Fibroplasia, caused concern. High oxygen concentrations appeared to be the causative factor (Cambell 1951). However, despite changes in oxygen administration and improvements in monitoring techniques, ROP remains a potential problem in neonatal units (Phelps 1992). The survival of extremely premature and low birth weight babies has led the incidence of ROP to increase, which leaves health professionals challenged by their inability to prevent its development.

Does my child really need to wear these glasses? a review of retinopathy of prematurity and long-term outcomes

Technological advances in neonatology create new challenges for patients, their families, and health care providers. Retinopathy of prematurity (ROP), a condition frequently seen in the premature infant, remains one of these challenges. Physiological stressors cause abnormal growth of retinal blood vessels and may result in vision loss. Common long-term sequelae include myopia, strabismus, and amblyopia; visual difficulties range from minor, correctible deficits to blindness. While research related to ROP continues, the question regarding long-term outcomes is a difficult one to answer for those families in the midst of this life-long challenge.

Eye therapy

The potential of gene delivery systems to treat eye disease stemming from abnormal blood vessel growth is reported by Itay Chowers in the British Journal of Ophthalmology (August issue). Induced retinopathy of prematurity (a disease increasing as a result of the rising numbers of surviving premature babies), is a leading cause of blindness and defective vision in children. The gene-delivery capabilities of four different viruses — adenovirus, bovine smallpox virus, herpes virus and the murine leukaemia virus — were tested in 18-day-old rats. Adenovirus was the most effective gene-transfer vector, with vaccinia coming in a close second. The murine leukaemia virus failed to deliver genes producing a functional product. DM

PEDF: Raising both hopes and questions in controlling angiogenesis

Depending on timing and venue, new blood vessel growth can be either beneficial or pathological. Vigorous vessel growth is absolutely necessary for tissue, organ, and limb development as was graphically demonstrated a few decades ago with thalidomide, now known to be a compound with antiangiogenic properties. As one ages though, the need for angiogenesis decreases or stops entirely except for specialized cases such as wound repair. In fact, neovascularization in the adult is usually associated with some form of pathology—tumor growth, for example, or diabetes. New work by Bouck and coworkers (1), as reported in PNAS, now gives evidence that a natural protein, pigment epithelium-derived factor (PEDF), is a potent inhibitor of abnormal blood vessel growth in a murine model of ocular neovascularization. This, together with previous data from the same group (2), gives compelling evidence that PEDF may be pivotal in controlling both normal and abnormal blood vessel growth. Although this gives hope for ultimately controlling neovascularization, it also raises interesting questions about PEDF's biological activities.

A mathematical model of growth factor induced capillary growth in the retina

Abnormal capillary growth in the retina has been recently associated with the presence of the Vascular Endothelial Growth Factor (VEGF). The production of VEGF is a result of oxygen starvation in the retina, which can take place as a consequence of inadequate capillary growth in premature babies or clogged capillaries in diabetics. When VEGF levels rise, they trigger abnormal blood vessel growth across the retina, and may cause damage, and sometimes permanent loss of vision. In this paper, a mathematical model that examines the effects of VEGF on the growth of retinal capillaries is presented. The model directly relates the production of VEGF to oxygen consumption. The diffusion equations for the concentrations of oxygen and VEGF are solved, and the capillary growth is determined as a function of the oxygen and VEGF concentrations.

Treatment of port-wine stains with the flashlamp-pumped pulsed dye laser: extended clinical experience in children and adults.

Seventy-six patients (51 females, 25 males) with port-wine stains (PWS) were treated with the flashlamp-pumped pulsed dye laser (585 nm, 450 microseconds). The patients ranged in age from 1 month to 71 years (average, 14 yr). Forty-nine percent of all patients under study had a 90% or better (average, 94.6%) lightening response after an average of 9.0 (range, 4-15) laser treatment. Overall, there was a 79% clinical improvement seen after an average of 9.1 (range, 2-19) laser treatments. In contrast to previous studies, the number of treatments necessary to obtain PWS clearing in older children (9-15 yr) and adults (> 16 yr) was not significantly greater than the number required to treat PWS in infants (0-2 yr) and younger children (3-8 yr). In fact, PWS in children aged 3 to 8 years required the greatest number of laser treatments, which may be due to continued abnormal growth of the ectatic blood vessels comprising the lesion during the growth of the child. In addition, there did not appear to be a significant difference in the number of laser treatments necessary to obtain clearing of PWS in different body locations. While the 585 nm pulsed dye laser continues to be the treatment of choice for removal of PWS in children and adults, the number of treatments necessary to obtain lesional clearing in all age groups in greater than previously reported.

Angiogenesis: State of the Art

Angiogenesis is the process by which new blood vessels are formed. This process occurs in the developing embryo,1 developing or growing tissue,2 wound healing and normal repair,3 inflammation,4 and a variety of pathologic processes which are accompanied by the abnormal growth of new blood vessels.5 Although the topic of angiogenesis has long been considered important, progress in understanding angiogenic mechanisms or in isolating angiogenic factors has, until recently, been quite slow. Rapid recent advances in angiogenesis research have stemmed largely from improvements in assay techniques which have resulted in the purification and identification of a number of distinct angiogenic factors.