Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data

AbstractThe angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development and maintenance. Its relevance to clinicians and basic scientists as a potential therapeutic target in retinal and choroidal vascular diseases is highlighted by recent preclinical and clinical evidence. The Ang/Tie pathway plays an important role in the regulation of vascular stability, in angiogenesis under physiological and pathological conditions, as well as in inflammation. Under physiological conditions, angiopoietin-1 (Ang-1) binds to and phosphorylates the Tie2 receptor, leading to downstream signalling that promotes cell survival and vascular stability. Angiopoietin-2 (Ang-2) is upregulated under pathological conditions and acts as a context-dependent agonist/antagonist of the Ang-1/Tie2 axis, causing vascular destabilisation and sensitising blood vessels to the effects of vascular endothelial growth factor-A (VEGF-A). Ang-2 and VEGF-A synergistically drive vascular leakage, neovascularisation and inflammation, key components of retinal vascular diseases. Preclinical evidence suggests that modulating the Ang/Tie pathway restores vascular stabilisation and reduces inflammation. This review discusses how targeting the Ang/Tie pathway or applying Ang-2/VEGF-A combination therapy may be a valuable therapeutic strategy for restoring vascular stability and reducing inflammation in the treatment of retinal and choroidal vascular diseases.

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Clinical Significance of Serum Levels of Vascular Endothelial Growth Factor, Angiopoietin-1, and Angiopoietin-2 in Patients with Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.090941 ◽

2010 ◽

Vol 37 (6) ◽

pp. 1121-1128 ◽

Cited By ~ 44

Author(s):

DAITARO KUROSAKA ◽

KENICHIRO HIRAI ◽

MAKIKO NISHIOKA ◽

YUKIO MIYAMOTO ◽

KEN YOSHIDA ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Serum Levels ◽

Vascular Endothelial ◽

Angiopoietin 2 ◽

Serum Crp ◽

Endothelial Growth Factor ◽

Vegf Level ◽

Angiopoietin 1

Objective.To evaluate the clinical significance of serum levels of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2) in patients with rheumatoid arthritis (RA).Methods.The subjects were 70 patients with RA. Serum VEGF, Ang-1, and Ang-2 levels were determined by ELISA. As indices of disease activity, serum levels of C-reactive protein (CRP) and matrix metalloprotease (MMP)-3 were examined, and the 28-joint count Disease Activity Score (DAS28)-CRP was calculated. Power Doppler ultrasonography was performed in the bilateral wrists, elbows, shoulders, knees and ankles. The synovial blood flow signals were scored using a 3-grade scale (0–2), and the total of the scores in the 10 joints was regarded as the total signal score (TSS).Results.Serum VEGF level showed significant correlations with serum CRP and MMP-3 levels, DAS28-CRP, and TSS. Serum Ang-1 level showed significant correlations with serum MMP-3 level and DAS28-CRP. Serum Ang-2 level showed significant correlations with serum CRP level and TSS.Conclusion.The serum VEGF level is important as an index of the activity of RA based on angiogenesis and a prognostic factor regarding joint destruction. Serum Ang-1 level may be useful as an index of sustained arthritis based on the maintenance of newly formed vessels. Serum Ang-2 level may reflect a state of marked angiogenesis.

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Plasma Vascular Endothelial Growth Factor, Angiopoietin-1, and Angiopoietin-2 in Diabetes: Implications for cardiovascular risk and effects of multifactorial intervention

Diabetes Care ◽

10.2337/diacare.27.12.2918 ◽

2004 ◽

Vol 27 (12) ◽

pp. 2918-2924 ◽

Cited By ~ 99

Author(s):

H. S. Lim ◽

A. D. Blann ◽

A. Y. Chong ◽

B. Freestone ◽

G. Y.H. Lip

Keyword(s):

Vascular Endothelial Growth Factor ◽

Cardiovascular Risk ◽

Growth Factor ◽

Vascular Endothelial ◽

Multifactorial Intervention ◽

Angiopoietin 2 ◽

Endothelial Growth Factor ◽

Angiopoietin 1

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Divergent regulation of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor by hypoxia and female sex steroids in human endometrial stromal cells

European Journal of Obstetrics & Gynecology and Reproductive Biology ◽

10.1016/j.ejogrb.2012.12.040 ◽

2013 ◽

Vol 168 (1) ◽

pp. 95-101 ◽

Cited By ~ 18

Author(s):

Tomoko Tsuzuki ◽

Hidetaka Okada ◽

Hisayuu Cho ◽

Kayo Shimoi ◽

Hiroe Miyashiro ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Stromal Cells ◽

Sex Steroids ◽

Vascular Endothelial ◽

Endometrial Stromal Cells ◽

Female Sex ◽

Angiopoietin 2 ◽

Endothelial Growth Factor ◽

Angiopoietin 1

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Localization of mRNA for vascular endothelial growth factor (VEGF), angiopoietins and their receptors during the peri-implantation period and early pregnancy in marmosets (Callithrix jacchus)

Reproduction ◽

10.1530/rep.0.1260227 ◽

2003 ◽

pp. 227-238 ◽

Cited By ~ 32

Author(s):

AJ Rowe ◽

C Wulff ◽

HM Fraser

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Early Pregnancy ◽

Glandular Epithelium ◽

Vascular Endothelial ◽

Angiopoietin 2 ◽

Endothelial Growth Factor ◽

Implantation Period ◽

Angiopoietin 1

Implantation of a blastocyst into a receptive endometrium is a prerequisite for successful pregnancy. Angiogenesis is a key event in this process but the mechanisms by which localized changes in vascular permeability and angiogenesis occur have yet to be elucidated. Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 have been implicated as key players in vascular remodelling and placentation. Angiopoietins also appear to have a significant role in regulation of blood vessel growth, maturation and regression. The aim of this study was to describe the molecular regulation of angiogenesis in the first month of pregnancy in marmosets and to address the putative physiological roles for these factors. Uteri were studied at weeks 2, 3 and 4 of pregnancy and compared with late secretory non-pregnant endometrium. Implantation in marmosets occurs at day 11 of pregnancy; hence, these time points were chosen so that the peri-implantation period and very early pregnancy could be studied. mRNAs for VEGF, VEGFR-1 and VEGFR-2, angiopoietin 1, angiopoietin 2 and their receptor Tie-2 were localized and quantified by in situ hybridization. Endothelial cells were identified by CD31 immunocytochemistry. VEGF mRNA was present in all compartments except endothelial cells, and its expression generally increased throughout pregnancy except in upper zone glandular epithelium and luminal epithelium, where a decrease in expression was observed. VEGF receptor mRNAs were found in endothelial cells of the upper zones immediately surrounding glandular epithelium. Angiopoietin 1 mRNA was localized to glandular epithelium of the upper and lower zones throughout pregnancy, and increased in stroma at week 4. Expression of angiopoietin 2 mRNA was localized exclusively to endothelial cells of large luminal vessels and was higher in endometrium from marmosets at week 4 of pregnancy than in endometrium from all other stages. These data provide comprehensive evidence that VEGFR-1 and -2, and angiopoietin 1, angiopoietin 2 and Tie-2 interactions may be involved in the preparation of endometrium for implantation, remodelling of the maternal vasculature and trophoblast invasion during the peri-implantation period in this primate species.

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