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PubMed2003

VEGF and PlGF: two pleiotropic growth factors with distinct roles in development and homeostasis.

Blood vessels are crucial for normal development and growth by providing oxygen and nutrients. As shown by genetic targeting studies in mice, zebrafish and Xenopus blood vessel formation (or angiogenesis) is a multistep process, which is highly dependent on angiogenic growth factors such as VEGF, the founding member of the VEGF family. VEGF binds to the tyrosine kinase receptors VEGFR-1 and VEGFR-2, and loss of VEGF or its receptors results in abnormal angiogenesis and lethality during development. In contrast, PlGF, another member of this family, binds only to VEGFR-1, and appears to be crucial exclusively for pathological angiogenesis in the adult. However, the expression of VEGFR-1 and VEGFR-2 on non-vascular cells suggests additional biological properties for these growth factors. Indeed, the VEGF family and its receptors determine development and homeostasis of many organs, including the respiratory, skeletal, hematopoietic, nervous, renal and reproductive system, independent of their vascular role. These new insights broaden the activity spectrum of these "angiogenic" growth factors, and may have therapeutic implications when using these growth factors for vascular and/or non-vascular purposes.

Animals↗

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↗

PubMed2004

Blocking Ca2+entry: a way to control cell proliferation.

Ca(2+) signalling is involved in virtually all cellular processes: among the others, it controls cell survival, proliferation and death regulating a plethora of intracellular enzymes located in the cytoplasm, nucleus and organelles. Changes in the cytosolic free Ca(2+) concentration may be due either to release from the intracellular Ca(2+) stores or to influx from the extracellular medium, through the opening of plasma membrane calcium-permeable channels. In particular, Ca(2+) entry from the extracellular space is a mechanism able to sustain long lasting intracellular Ca(2+) elevations: this signal, activated by many growth factors and mitogens in normal and tumoral tissues, is linked to DNA transcription and duplication, finally leading to cell proliferation. In the last years many informations have been provided about the transduction mechanisms related to Ca(2+) entry induced by mitogenic factors, mostly binding to tyrosine kinase receptors, but also to G-protein coupled ones. Nevertheless, some key points remain to be fully clarified: among them, the molecular structure of the Ca(2+) channels involved, their regulation by intracellular messengers, and the modes through which specificity is achieved. The increasing knowledge on Ca(2+) entry-dependent control of proliferation may provide a more satisfactory understanding of pathological alterations, including cancer progression and angiogenesis. A detailed description of the mechanisms that trigger Ca(2+) entry, and in particular the definition of calcium-permeable channels and their modulators at the molecular levels, will greatly improve our possibility to take advantage of Ca(2+) entry regulation as a therapeutic approach for the control of cell proliferation, designing antibodies or molecules with low side effects and specific channel blocker functions. The review will focus on this topic.

Animals↗

PubMed1996

Angiogenesis and the skin: a primer.

Angiogenesis is the development of a blood supply to a given area of tissue. This area of tissue may be part of normal embryonic development, revascularization of a wound bed, or the stimulation of vessel growth by inflammatory or malignant cells. Angiogenesis is of crucial importance to the dermatologist, as it is of key importance in pathologic processes such as psoriasis, warts, and cutaneous malignancy, and it is required for optimal wound healing. Other dermatologic processes wherein angiogenesis is defective or uncontrolled are decubitus ulcers, stasis ulcers, pyogenic granulomas, hemangiomas, Kaposi's sarcoma, and possibly Spitz nevus, hypertrophic scars, and keloids. Recent advances in the understanding of growth factors will likely lead to advances in the treatment of skin cancer and psoriasis, and more rapid healing of wounds. In this review, I hope to summarize the most important growth factors, inhibitors of angiogenesis, and future directions in research and therapeutics involving angiogenesis.

Animals↗

PubMed2003

Regulation of vascular development by fibroblast growth factors.

Fibroblast growth factors (FGFs) are potent stimulators of angiogenesis in vitro and in vivo. However, the precise role of FGFs and vascular development in normal and pathological tissue has long remained ill defined. Recently, substantial progress has been made toward a better understanding of their role. Genetic studies in mice or in culture systems indicate a role for FGFs in vessel assembly and sprouting. FGFs also stimulate blood vessel branching and lymphangiogenesis. The molecular mechanisms by which FGFs mediate angiogenesis are also better understood. Finally, the FGF/FGF-receptor system has become a focus for the development of novel therapeutic strategies for the treatment of angiogenesis-related diseases such as tissue ischemia.

Animals↗

PubMed2000

RACK1 is up-regulated in angiogenesis and human carcinomas.

Angiogenesis is crucial for many biological and pathological processes including the ovarian cycle and tumor growth. To identify molecules relevant for angiogenesis, we performed mRNA fingerprinting and subsequent Northern blot analysis using bovine cord-forming vs. monolayer-forming endothelial cells (EC) in vitro and staged bovine corpora lutea in vivo. We detected the receptor for activated C kinase 1 (RACK1), the specific receptor for activated protein kinase C beta (PKC beta), to be up-regulated in bovine cord-forming EC in vitro and in angiogenically active stages of bovine corpora lutea in vivo. Thereafter we established and determined the complete bovine RACK1 cDNA sequence. RACK1 was massively induced in subconfluent vs. contact-inhibited bovine EC, during angiogenesis in vitro, active phases of the murine ovarian cycle, human tumor angiogenesis, and in cancer cells in vivo as assessed by quantitative PCR and in situ hybridization. RACK1 transcripts were localized to proliferating EC in vitro and the endothelium of tumor neovascularizations in vivo by in situ hybridization. PKC beta plays an important role in angiogenesis and cancer growth. Our data suggest that downstream signaling of PKC beta in angiogenically active vs. inactive tissues and endothelium is affected by the availability of RACK1.

Animals↗

PubMed2005

Endogenous inhibitors of angiogenesis.

Angiogenesis, the formation of new blood vessels, is required for many pathologic processes, including invasive tumor growth as well as physiologic organ/tissue maintenance. Angiogenesis during development and adulthood is likely regulated by a balance between endogenous proangiogenic and antiangiogenic factors. It is speculated that tumor growth requires disruption of such balance; thus, the angiogenic switch must be turned "on" for cancer progression. If the angiogenic switch needs to be turned on to facilitate the tumor growth, the question remains as to what the physiologic status of this switch is in the adult human body; is it "off," with inhibitors outweighing the stimulators, or maintained at a fine "balance," keeping the proangiogenic properties of many factors at a delicate "activity" balance with endogenous inhibitors of angiogenesis. The physiologic status of this balance is important to understand as it might determine an individual's predisposition to turn the switch on during pathologic events dependent on angiogenesis. Conceivably, if the physiologic angiogenesis balance in human population exists somewhere between off and even balance, an individual's capacity and rate to turn the switch on might reflect their normal physiologic angiogenic status. In this regard, although extensive knowledge has been gained in our understanding of endogenous growth factors that stimulate angiogenesis, the activities associated with endogenous inhibitors are poorly understood. In this review, we will present an overview of the knowledge gained in studies related to the identification and characterization of 27 different endogenous inhibitors of angiogenesis.

Angiogenesis Inhibitors↗

PubMed2001

[The mechanisms of angiogenesis. Medical and therapeutic applications].

PURPOSE: Endothelial and smooth muscle cells interact with each other to form new blood vessels. In this review, the cellular and molecular mechanism underlying the formation of the primary vascular plexus (vasculogenesis), the sprouting of further blood vessels (angiogenesis) and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized. CURRENT KNOWLEDGE AND KEY POINT: The concept of angiogenesis is studied in tumoral and cardiovascular pathology. Promoting the formation of new collateral vessels in ischemic tissues using angiogenic growth factors (therapeutic angiogenesis) is a promising approach in cardiovascular diseases. Conversely, inhibition of the action of key regulators of angiogenesis is a new pathway for the treatment of solid tumors and metastasis. FUTURE PROSPECTS AND PROJECTS: These concepts are being tested now in clinical trials in the oncology or cardiovascular fields. Some trials are reported in this review with their potential adverse effects, limits and developments in the future.

Angiogenesis Inducing Agents↗

PubMedDate not supplied

The clinical implications of angiogenesis in the treatment of cancer.

Angiogenesis, the formation of new blood vessels from pre-existing ones, is a very well controlled multistep process under physiologic conditions. It involves a balance between several positive and negative regulators. Pathologic angiogenesis, both excessive and insufficient, plays a role in the pathophysiology of many diseases including cancer. It has been proven that tumor growth and metastasis are angiogenesis-dependent. Endothelial cells and tumor cells also provide a mutual support to each other via the secretion of several substances. Targeting tumor blood vessels is a new approach to the treatment of cancer. Clinical trials are currently underway and the results appear to be very promising.

Angiogenesis Inducing Agents↗

PubMed2005

The biology of vascular endothelial growth factors.

The discovery of the vascular endothelial growth factor (VEGF) family members VEGF, VEGF-B, placental growth factor (PlGF), VEGF-C and VEGF-D and their receptors VEGFR-1, -2 and -3 has provided tools for studying the vascular system in development as well as in diseases ranging from ischemic heart disease to cancer. VEGF has been established as the prime angiogenic molecule during development, adult physiology and pathology. PlGF may primarily mediate arteriogenesis, the formation of collateral arteries from preexisting arterioles, with potential future therapeutic use in for example occlusive atherosclerotic disease. VEGF-C and VEGF-D are primarily lymphangiogenic factors, but they can also induce angiogenesis in some conditions. While many studies have addressed the role of angiogenesis and the blood vasculature in human physiology, the lymphatic vascular system has until recently attracted very little attention. In this review, we will discuss recent advances in angiogenesis research and provide an overview of the molecular players involved in lymphangiogenesis.

Cardiovascular Diseases↗

PubMed2005

Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies.

Angiogenesis is a process by which new blood vessels are formed from preexisting vessels. New blood vessel formation by angiogenesis involves the degradation of extra-cellular matrix combined with sprouting and migration of endothelial cells from preexisting capillaries. Solid tumors consist of several components, including normal and stromal cells, extracellular matrix, and vasculature. To grow and metastasize, tumors must stimulate the development of new vasculature through angiogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine regeneration. VEGF is both a vascular growth factor and a vascular permeability factor. Its expression can upregulate several proangiogenic and prometa-static molecules. As a central mediator of angiogenesis, VEGF has emerged as an important target for antiangiogenic therapy. In this review, the authors describe the essential characteristics of VEGF and the VEGF family of ligands and their receptors. They also provide an overview of the central role of VEGF in physiologic and pathologic angiogenesis, directly or indirectly. This review sheds light on the importance of VEGF-targeted antiangiogenic therapy based on the monoclonal antibodies against VEGF, small interfering RNA, and therapy directed against VEGF-VEGFR kinase. It also gives a brief overview of the natural products or dietary compounds that could be used as antiangiogenic agents. Therapeutic inhibition of vessel formation could be best suited to preventive strategies aimed at the suppression of angiogenesis in primary tumors in subjects at risk or of micrometastases after surgical removal of primary tumor.

Angiogenesis Inhibitors↗

PubMed2006

CCN family proteins and angiogenesis: from embryo to adulthood.

The CCN family is a novel class of extracellular signal modulators that has been recently established. Typical members are composed of four conserved modules connected tandem, each of which is rich in cysteines and highly interactive with other molecules. The mammalian CCN family consists of six members, most of which have been described as multifunctional factors for the developmental process of mesenchymal tissue including blood vessel formation/induction. Particularly, the angiogenic properties of the three classical members, CCN1, 2 and 3 have so far been characterized, and their physiological and pathological significance has thus been indicated. Recent research has uncovered a unique mechanism regarding these proteins in promoting and/or modulating developmental, physiological and pathological angiogenic events. Namely, CCN proteins exert their ability to drive angiogenesis, not by stimulating a particular behavior of a particular type of cells, but by manipulating the cell communication networks that integrate most of the associated molecules/cells toward angiogenesis. In this article, the role of the CCN proteins in a variety of angiogenic events as an organizer of microenvironmental cell society is comprehensively described, together with a brief summary of the recent findings on each CCN family member relevant to angiogenesis including cardiovascular development and diseases.

Animals↗

PubMedDate not supplied

Vascular endothelial growth factor: a key mediator of neoangiogenesis. A review.

Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that exerts in vivo a key role in physiological and pathological neoangiogenesis by stimulating endothelial cell proliferation and vessel hyperpermeability. VEGF exists as one of four different isoforms, respectively, VEGF 121, VEGF 165, VEGF 189, VEGF 206, and seems to be a crucial mediator of physiological neoangiogenesis during the embryonic development and the female cycle. VEGF also has a major role in the pathogenesis of many diseases including hypervascularized tumors, rheumatoid arthritis, cutaneous diseases and proliferative retinopathies. Anti-VEGF anti-bodies or VEGF agonists may represent a novel approach in the treatment of these diseases.

Animals↗

PubMed2000

Vascular endothelial growth factor and the regulation of angiogenesis.

The development of a vascular supply is essential not only for organ development and differentiation during embryogenesis but also for wound healing and reproductive functions in the adult Folkman, 1995). Angiogenesis is also implicated in the pathogenesis of a variety of disorders: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis (Folkman, 1995; Garner, 1994). Several potential regulators of angiogenesis have been identified, including fibroblast growth factor-a (aFGF), bFGF, transforming growth factor-alpha (TGF-alpha), TGF-beta, hepatocyte growth factor/scatter factor (HGF/SF), tumor necrosis factor-alpha (TNF-alpha), angiogenin, and interleukin-8 (IL-8) (Folkman and Shing, 1992; Risau, 1997). More recently, the angiopoietins, the ligands of the Tie-2 receptor (Suri et al., 1996; Maisonpierre et al., 1997), have been identified. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific mitogen. The finding that VEGF was potent and specific for vascular endothelial cells and, unlike bFGF, freely diffusible, led to the hypothesis that this molecule plays a unique role in the regulation of physiological and pathological angiogenesis (Ferrara and Henzel, 1989: Leung et al., 1989). Over the last few years, several additional members of the VEGF gene family have been identified, including placenta growth factor (PIGF) (Maglione et al., 1991,1993), VEGF-B (Olofsson et al., 1996), VEGF-C (Joukov et al., 1996; Lee et al., 1996), and VEGF-D (Orlandini et al., 1996. Achen et al., 1998). There is compelling evidence that VEGF plays an essential role in the development and differentiation of the cardiovascular system (Ferrara and Davis-Smyth, 1997).

Adult↗

PubMed2000

Regulation of VEGF in the reproductive tract by sex-steroid hormones.

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis. In adults, angiogenesis is an infrequent event in the normal tissue except in the female reproductive tract where angiogenesis occurs frequently during the cyclical repair and regeneration of the endometrium as well as in the ovary. Little is known about angiogenesis in the male reproductive tract. The role of VEGF in controlling reproductive tract physiology and the role of hormones in regulating this key regulator of angiogenesis is not well understood. Since reproductive tract physiology is largely under sex-steroid regulation, we have reviewed some recent studies describing the role of sex-steroid hormones in regulating VEGF. We have also included studies on the role of sex-steroids in regulating VEGF and angiogenesis in endometrial, breast and prostate pathologies. We have provided an extensive review of the classical VEGF and VEGF receptors with examples drawn from numerous studies in the literature using diverse biological systems to encourage similar studies in the area of reproductive tract physiology. It is speculated that such studies will provide insights into understanding the role of VEGF in reproductive tract development, causes of infertility, and cancer. Such knowledge would allow us to target VEGF for improving human reproductive tract abnormalities, for enhancing implantation and fertility, and for designing drugs for treatment of endocrine dependent cancers.

Adult↗

PubMed2004

Vascular endothelial growth factor (VEGF) in physiological and pathological conditions.

Vascular endothelial growth factor (VEGF) is the major endothelial-cell specific stimulatory factor regarded as the most important positive regulator of angiogenesis and vascular permeability. Due to its powerful angiogenic and mitogenic properties, VEGF takes part in a variety of crucial biological processes, including wound repair and tumorigenesis. The elevated expression of VEGF and its receptors has been found in malignancies of various origin as being associated with metastasis formation and poor prognosis. Recently, some possibilities appeared to block the VEGF action when it is undesirable or promote its activity when it can be useful. These new therapeutic strategies based upon the knowledge of VEGF biological role, are being tried and up till now they proved to be successful, especially in anticancer therapy and the coronary heart disease treatment.

Animals↗

PubMed2006

New vessel formation in the central nervous system during tumor growth, vascular malformations, and Moyamoya.

In the normal adult brain, blood vessel formation is tightly down-regulated. However, pathologic processes such as brain tumors can increase the proportion of endothelial cells involved in angiogenesis. When this process is initiated, a complex series of timed events result in new vessel formation. In this review, we will describe the process of angiogenesis in the central nervous system. We will discuss the roles of Vascular Endothelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF), Angiopoietins, Platelet Derived Growth Factor (PDGF), and integrins in angiogenesis. We will also look into their significance in disease processes such as neoplasms, arteriovenous malformations (AVM), and Moyamoya disease.

Angiopoietins↗

PubMed2005

The crucial role of vascular permeability factor/vascular endothelial growth factor in angiogenesis: a historical review.

Angiogenesis is a biological process by which new capillaries are formed and it occurs in many physiological and pathological conditions. It is controlled by the net balance between molecules that have positive and negative regulatory activity and this concept had led to the notion of the 'angiogenic switch', depending on an increased production of one or more of the positive regulators of angiogenesis. Numerous inducers of angiogenesis have been identified and this review offers a historical account of the relevant literature concerning the discovery of one of the best characterized angiogenic factors, namely vascular endothelial growth factor (VEGF)/vascular permeability factor. Moreover, different strategies, designed to stimulate and to inhibit VEGF production in the context of several potential therapeutical implications, are discussed.

Angiogenesis Inducing Agents↗