Integrins and Angiogenesis
Introduction
Blood vessels develop from at least two processes, termed vasculogenesis and angiogenesis (Isner and Asahara, 1999). Vasculogenesis is the process by which blood vessels form de novo, during development, as the nascent vascular bed arises from hematopoietic precursor angioblasts (Drake et al., 1995). By contrast, angiogenesis occurs as the growth or sprouting of new blood vessels from a pre-existing vascular bed. Although angiogenesis is generally accepted to be the principle mechanism of blood vessel growth within the adult, it has recently become clear that the recruitment of hematopoietic precursors is a critical event during angiogenesis, suggesting a previously unsuspected vasculogenic component (Ribatti et al., 2001). Thus, the distinction between these processes has blurred somewhat, and many of the mechanisms that regulate angiogenesis may be common to both processes (Rupp et al., 2003).
Neovascularization is a tightly regulated process during development and wound repair but appears considerably less regulated during pathological angiogenesis associated with cancer and inflammatory disease. However, normal or “unactivated” blood vessels in the adult are relatively quiescent and nonproliferative. The endothelial cells lining the inner surface of the blood vessels maintain tight cell–cell junctions and stable interactions with the underlying extracellular matrix (ECM), or basement membrane. These endothelial cells exhibit a very low mitotic index. Cell cycle entry occurs in only about 1 in 1000 cells, replacing endothelial cells lost through routine attrition (Folkman and Klagsbrun, 1987). In contrast to this resting state, endothelial cells stimulated with angiogenic growth factors such as vascular endothelial cell growth factor (VEGF) (Dvorak 1995, Ferrara 2003) or basic fibroblast growth factor (bFGF) (Folkman et al., 1988) become highly proliferative, achieving mitotic indices similar to growing tumors. Concomitant with accelerated proliferation, increased transcription and protein synthesis also occur, as endothelial cells prepare for cell migration⧸invasion and neovessel outgrowth.
In addition to the increased expression of cell cycle proteins, angiogenic endothelial cells express a repertoire of new proteins, including transcription factors such as Hox (Myers et al., 2000) and Id genes (Benezra et al., 2001), which in turn regulate the expression of integrins and production of new provisional ECM components, matrix-proteolyzing enzymes (Heissig et al., 2003), their inhibitors (Mannello and Gazzanelli, 2001), as well as growth factors and apoptosis-regulating proteins (reviewed in Dimmeler and Zeiher, 2000). Physiologically, angiogenic endothelial cells exhibit an increased capacity to proliferate and invade tissue, but perhaps somewhat surprisingly, demonstrate an increased predisposition to undergo apoptosis (Brooks 1994a, Brooks 1994b). Previous reports suggested that proper blood vessel formation depends on a balance between endothelial cell proliferation and apoptosis (reviewed in Stupack and Cheresh, 2003). The regulation of these processes is closely tied to remodeling events in the local ECM and to integrins that enable endothelial cells to respond to the ECM.
Section snippets
Integrin Structure
Integrins are heterodimeric receptors that mediate divalent cation-dependent cell attachment to the ECM, but that can also interact with cell surface and soluble ligands. Nascent integrin α and β subunits are paired in the endoplasmic reticulum to form functional heterodimers, which then traffick to the cell surface (Cheresh, 1992). While there are at least 18 different α subunits and 8 different β subunits, only 24 different α⧸β combinations have been observed. Each α⧸β heterodimer has its own
Initiation of Angiogenesis
The transition from resting to angiogenic endothelium requires a trigger to activate the cellular programs of proliferation and protein synthesis required for neovessel formation. In addition to bFGF and VEGF, mentioned previously, a growing list of proangiogenic factors have now been identified, including glycoproteins (Zhong et al., 2003), complex carbohydrates (Presta et al., 2003), and bioactive lipids (Hla et al., 2000), in addition to well-established proangiogenic growth factors such as
Alterations in Integrin–ECM Interactions During Angiogenesis
The transcriptional programs activated by proangiogenic growth factors result in the synthesis and release of new ECM components as well as ECM-digesting enzymes from endothelial cells and in some cases also from the surrounding tumor and⧸or stromal cells themselves. A number of proteases become associated with the endothelial cell surface, and upon activation, cleave ECM components, process other protease zymogens, or do both. However, proteases such as MMPs may release growth factors such as
Integrin Antagonists Effects versus the Phenotype of Knockout Animals
Allosteric antagonists or small molecule agonists of αv integrins block angiogenesis in multiple species (reviewed in Rupp et al., 2003) and disrupt vasculogenesis during avian development (Drake et al., 1995). In contrast with these results, mice lacking αvβ3 show no obvious vascular defect during development (Hodivala-Dilke et al., 1999). This is, however, consistent with the observation that this integrin is known to be deficient in some forms of Glanzmann's thrombaesthenia in human disease (
Current Clinical Perspective
There are at lease three integrin antagonists currently undergoing clinical trials for a number of diseases associated with angiogenesis. The first of these agents to enter clinical testing was Vitaxin, the fully humanized form of monoclonal antibody LM609 directed against integrin αvβ3. In an early phase I trial, Vitaxin was shown to promote disease stabilization in more than half of the patients (Gutheil et al., 2000). All of the patients had progressive disease and had failed multiple
References (136)
- et al.
Distinct roles of the adaptor protein Shc and focal adhesion kinase in integrin signaling to ERK
J. Biol. Chem
(2000) - et al.
The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis
J. Biol. Chem
(2004) - et al.
Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels
Cell
(1994) - et al.
Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity
Cell
(1998) - et al.
Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3
Cell
(1996) - et al.
Direct cell adhesion to the angiopoietins mediated by integrins
J. Biol. Chem
(2001) - et al.
The alpha(2) integrin subunit-deficient mouse: A multifaceted phenotype including defects of branching morphogenesis and hemostasis
Am. J. Pathol
(2002) Structural and biologic properties of integrin-mediated cell adhesion
Clin. Lab. Med
(1992)- et al.
Beta 1 and beta 3 integrins have different roles in the adhesion and migration of vascular smooth muscle cells on extracellular matrix
Exp. Cell. Res
(1992) - et al.
Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel
Blood
(1991)
Integrin signaling: It's where the action is
Curr. Opin. Cell Biol
Affinity of integrins for damaged extracellular matrix: Alpha v beta 3 binds to denatured collagen type I through RGD sites
Biochem. Biophys. Res. Commun
Perturbation of beta 1 integrin-mediated adhesions results in altered somite cell shape and behavior
Dev. Biol
Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability
Mol. Cell
Plasminogen activation at the cell surface
Curr. Top. Dev. Biol
PI3K: Downstream AKTion blocks apoptosis
Cell
Deletion of integrin alpha 1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion
Dev. Biol
A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho⧸TLE corepressors
Cell
Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin
Am. J. Pathol
Identification of the anti-angiogenic site within vascular basement membrane-derived tumstatin
J. Biol. Chem
A signaling pathway from the alpha5beta1 and alpha(v)beta3 integrins that elevates bcl-2 transcription
J. Biol. Chem
Signaling through JAM-1 and alphavbeta3 is required for the angiogenic action of bFGF: Dissociation of the JAM-1 and alphavbeta3 complex
Blood
VEGF(121) and VEGF(165) regulate blood vessel diameter through vascular endothelial growth factor receptor 2 in an in vitro angiogenesis model
Lab. Invest
Cell receptors involved in adenovirus entry
Virology
Endostatin: An endogenous inhibitor of angiogenesis and tumor growth
Cell
Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma
Cell
Src family protein tyrosine kinases: Cooperating with growth factor and adhesion signaling pathways
Curr. Opin. Cell Biol
Del1 induces integrin signaling and angiogenesis by ligation of alphaVbeta3
J. Biol. Chem
New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo
J. Biol. Chem
Postnatal vasculogenesis
Mech Dev
Role of Raf in vascular protection from distinct apoptotic stimuli
Science
Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties
Biol. Chem
Magnetic resonance contrast enhancement of neovasculature with alpha(v)beta(3)-targeted nanoparticles
Magn. Reson. Med
Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model
Science
The integrin-linked kinase (ILK) suppresses anoikis
Oncogene
The Id proteins and angiogenesis
Oncogene
Evidence that beta3 integrin-induced Rac activation involves the calpain-dependent formation of integrin clusters that are distinct from the focal complexes and focal adhesions that form as Rac and RhoA become active
J. Cell Biol
Induction of the angiogenic phenotype by Hox D3
J. Cell Biol
Expression of the beta 7 integrin by human endothelial cells
Am. J. Pathol
Requirement of vascular integrin alpha v beta 3 for angiogenesis
Science
Insulin-like growth factor receptor cooperates with integrin alpha v beta 5 to promote tumor cell dissemination in vivo
J. Clin. Invest
Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin
J. Clin. Invest
Sprouty proteins: Antagonists of endothelial cell signaling and more
Thromb. Haemost
Alpha4beta1 integrin mediates selective endothelial cell responses to thrombospondins 1 and 2 in vitro and modulates angiogenesis in vivo
Circ. Res
Elevated levels of urine angiostatin and plasminogen⧸plasmin in cancer patients
Int. J. Mol. Med
The vitronectin receptor alpha v beta 3 binds fibronectin and acts in concert with alpha 5 beta 1 in promoting cellular attachment and spreading on fibronectin
J. Cell Biol
Human endothelial cells synthesize and express an Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand factor
Proc. Natl. Acad. Sci. USA
Integrin-mediated death: An explanation of the integrin-knockout phenotype?
Nat. Med
Endothelial cell apoptosis in angiogenesis and vessel regression
Circ. Res
An antagonist of integrin alpha v beta 3 prevents maturation of blood vessels during embryonic neovascularization
J. Cell Sci
Cited by (266)
To improve the angiogenesis of endothelial cells on Ti-Cu alloy by the synergistic effects of Cu ions release and surface nanostructure
2022, Surface and Coatings TechnologyEndothelial dysfunction: basis for many local and systemic conditions
2022, The Vasculome: From Many, OneIn vitro analysis of the trajectories of adhesive microbubbles approaching endothelial cells
2020, Journal of Colloid and Interface ScienceImmune-Mediated Cytopenia in the Pediatric Setting
2020, Immunologic Concepts in Transfusion MedicineRole of angiogenesis in melanoma progression: Update on key angiogenic mechanisms and other associated components
2019, Seminars in Cancer Biology