Confocal Microscopic Analysis of Integrin Expression on the Microvasculature and its Sprouts in the Neonatal Foreskin

Enenstein, Judy; Kramer, Randall H.

doi:10.1111/1523-1747.ep12395390

Cited by 73 publications

(27 citation statements)

References 31 publications

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“…However, integrin function can require activation through signaling pathways inside the cell, and therefore expression of a particular integrin need not correlate with functional activity (32,52). Furthermore, and consistent with findings reported here, ␣ 1 ␤ 1 was found to be overexpressed by tumor blood vessels (53) and increased expression of ␣ 2 ␤ 1 was demonstrated at the sprouting tips of neonatal blood vessels (54). Thus, it is an intriguing possibility that ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrins are expressed by quiescent microvascular endothelium in low abundance relative to stimulated endothelium and also that they are less active and therefore less influenced by ␣ 1 ␤ 1 and ␣ 2 ␤ 1 antagonists.…”

Section: Discussionsupporting

confidence: 73%

Angiogenesis promoted by vascular endothelial growth factor: Regulation through α₁β₁and α₂β₁integrins

Senger

Claffey

Benes

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

492

349

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Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a cytokine of central importance for the angiogenesis associated with cancers and other pathologies. Because angiogenesis often involves endothelial cell (EC) migration and proliferation within a collagen-rich extracellular matrix, we investigated the possibility that VEGF promotes neovascularization through regulation of collagen receptor expression. VEGF induced a 5-to 7-fold increase in dermal microvascular EC surface protein expression of two collagen receptors-the ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrins-through induction of mRNAs encoding the ␣ 1 and ␣ 2 subunits. In contrast, VEGF did not induce increased expression of the ␣ 3 ␤ 1 integrin, which also has been implicated in collagen binding. Integrin ␣ 1 -blocking and ␣ 2 -blocking antibodies (Ab) each partially inhibited attachment of microvascular EC to collagen I, and ␣ 1 -blocking Ab also inhibited attachment to collagen IV and laminin-1. Induction of ␣ 1 ␤ 1 and ␣ 2 ␤ 1 expression by VEGF promoted cell spreading on collagen I gels which was abolished by a combination of ␣ 1 -blocking and ␣ 2 -blocking Abs. In vivo, a combination of ␣ 1 -blocking and ␣ 2 -blocking Abs markedly inhibited VEGF-driven angiogenesis; average cross-sectional area of individual new blood vessels was reduced 90% and average total new vascular area was reduced 82% without detectable effects on the pre-existing vasculature. These data indicate that induction of ␣ 1 ␤ 1 and ␣ 2 ␤ 1 expression by EC is an important mechanism by which VEGF promotes angiogenesis and that ␣ 1 ␤ 1 and ␣ 2 ␤ 1 antagonists may prove effective in inhibiting VEGF-driven angiogenesis in cancers and other important pathologies.

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Section: Discussionsupporting

confidence: 73%

Angiogenesis promoted by vascular endothelial growth factor: Regulation through α₁β₁and α₂β₁integrins

Senger

Claffey

Benes

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

492

349

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“…Does ␣ 6 ␤ 1 play a role in angiogenesis? In vivo expression studies demonstrated that ␣ 6 integrins are highly expressed in capillary endothelial cells (48), although ␣ 6 ␤ 1 and ␣ 6 ␤ 4 could not be distinguished by this method. The ␣ 6 null mouse is not informative for this issue because ␣ 6 ␤ 4 plays a critical role in 5 /well) added to the upper chamber were allowed to migrate for 6 h at 37°C in 5% CO 2 .…”

Section: Discussionmentioning

confidence: 88%

Recognition of the N-terminal Modules of Thrombospondin-1 and Thrombospondin-2 by α6β1 Integrin

Calzada

Sipes

Krutzsch

et al. 2003

Journal of Biological Chemistry

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In addition to its recognition by ␣ 3 ␤ 1 and ␣ 4 ␤ 1 integrins, the N-terminal pentraxin module of thrombospondin-1 is a ligand for ␣ 6 ␤ 1 integrin. ␣ 6 ␤ 1 integrin mediates adhesion of human microvascular endothelial and HT-1080 fibrosarcoma cells to immobilized thrombospondin-1 and recombinant N-terminal regions of thrombospondin-1 and thrombospondin-2. ␣ 6 ␤ 1 also mediates chemotaxis of microvascular cells to thrombospondin-1 and thrombospondin-2. Using synthetic peptides, LALERKDHSG was identified as an ␣ 6 ␤ 1 -binding sequence in thrombospondin-1. This peptide inhibited ␣ 6 ␤ 1 -dependent cell adhesion to thrombospondin-1, thrombospondin-2, and the E8 fragment of murine laminin-1. The Glu residue in this peptide was required for activity, and the corresponding residue (Glu 90 ) in the N-terminal module of thrombospondin-1 was required for its recognition by ␣ 6 ␤ 1 , but not by ␣ 4 ␤ 1 . ␣ 6 ␤ 1 was also expressed in human umbilical vein endothelial cells; but in these cells, only certain agonists could activate the integrin to recognize thrombospondins. Selective activation of ␣ 6 ␤ 1 integrin in microvascular endothelial cells by the anti-␤ 1 antibody TS2/16 therefore accounts for their adhesion responses to thrombospondins and explains the distinct functions of ␣ 4 ␤ 1 and ␣ 6 ␤ 1 integrins as thrombospondin receptors in microvascular and large vessel endothelial cells.

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“…These phenotypic differences are reflected by differences in gene expression: for example, tip cells are enriched for VEGFR2, neuropilin-1 and -2, PDGFB, the netrin receptor Unc5B, and the integrins ␣ 6 and ␤ 4 . 36,38,57,58 We and others have shown that notch signaling plays a critical role in the determination of tip cells, and loss of signaling, due to chemical inhibition or loss of dll4 expression, leads to EC hyperproliferation, excessive vascular branching, and an overabundance of tip cells. [22][23][24][25][26][27] Dll4 expression appears, therefore, to mark vessels undergoing active growth in the retina and in zebrafish.…”

Section: Gene Expression In Tip Cellsmentioning

confidence: 99%

TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype

Sainson

Johnston

Chu

et al. 2008

Blood

279

253

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Pathological angiogenesis associated with wound healing often occurs subsequent to an inflammatory response that includes the secretion of cytokines such as tumor necrosis factor (TNF). Controversy exists on the angiogenic actions of TNF, with it being generally proangiogenic in vivo, but antiangiogenic in vitro. We find that whereas continuous administration of TNF in vitro or in vivo inhibits angiogenic sprouting, a 2-to 3-day pulse stimulates angiogenesis by inducing an endothelial "tip cell" phenotype. TNF induces the known tip cell genes plateletderived growth factor B (PDGFB) and vascular endothelial cell growth factor receptor-2 (VEGFR2), while at the same time blocking signaling through VEGFR2, thus delaying the VEGF-driven angiogenic response. Notch signaling regulates tip cell function, and we find that TNF also induces the notch ligand jagged-1, through an NFB-dependent mechanism. Enrichment of jagged-1 in tip cells was confirmed by immunofluorescent staining as well as by laser capture microdissection/quantitative reversetranscription-polymerase chain reaction IntroductionNeovascularization, or the formation of new blood vessels, is a critical component of many physiologic as well as pathologic conditions, including development, reproduction, wound healing, diabetic retinopathy, and tumor growth. During wound healing, new vessel growth by angiogenesis is a necessary early step in rebuilding tissue, however the coordination of angiogenesis with the resolution of the acute inflammatory stage is not well understood. The earliest events after tissue damage include the generation of a fibrin clot and the bursting of platelets to release numerous growth factors. Fibrin provides a provisional matrix that promotes the accumulation of blood-derived monocytes that then differentiate into tissue macrophages. Activated macrophages synthesize several cytokines, including tumor necrosis factor (TNF), which activate local endothelial cells (ECs) and promote leukocyte recruitment. After 3 to 4 days, when the initial infection has been cleared, there is a switch toward tissue repair and concomitant with this is the acceleration of angiogenesis. 1,2 TNF is a major inflammatory mediator that induces multiple changes in EC gene expression including induction of adhesion molecules, integrins, and matrix metalloproteinases (MMPs). Its effects on angiogenesis have been the subject of some controversy. For example, TNF blocks EC proliferation and migration in vitro [3][4][5] and has been reported to down-regulate activity 6 and expression 7,8 of vascular endothelial cell growth factor receptor-2 (VEGFR2). On the other hand, TNF has also been shown to up-regulate VEGFR2 expression 9 and promote EC migration. 10 In vivo the situation is no clearer: TNF promotes angiogenesis in the cornea, 3,11 whereas loss of TNFR1 (p55 receptor) leads to enhanced angiogenesis in both retina 12 and wounded skin. 13 Further studies with TNF receptor-deficient mice have demonstrated enhanced hind limb angiogenesis after temporary ischemia in T...

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Confocal Microscopic Analysis of Integrin Expression on the Microvasculature and its Sprouts in the Neonatal Foreskin

Cited by 73 publications

References 31 publications

Angiogenesis promoted by vascular endothelial growth factor: Regulation through α₁β₁and α₂β₁integrins

Angiogenesis promoted by vascular endothelial growth factor: Regulation through α₁β₁and α₂β₁integrins

Recognition of the N-terminal Modules of Thrombospondin-1 and Thrombospondin-2 by α6β1 Integrin

TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype

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Confocal Microscopic Analysis of Integrin Expression on the Microvasculature and its Sprouts in the Neonatal Foreskin

Cited by 73 publications

References 31 publications

Angiogenesis promoted by vascular endothelial growth factor: Regulation through α1β1and α2β1 integrins

Angiogenesis promoted by vascular endothelial growth factor: Regulation through α1β1and α2β1 integrins

Recognition of the N-terminal Modules of Thrombospondin-1 and Thrombospondin-2 by α6β1 Integrin

TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype

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Angiogenesis promoted by vascular endothelial growth factor: Regulation through α₁β₁and α₂β₁integrins

Angiogenesis promoted by vascular endothelial growth factor: Regulation through α₁β₁and α₂β₁integrins