The Angiopoietin/Tie-2 System Regulates Pericyte Survival and Recruitment in Diabetic Retinopathy

Cai, Jun; Kehoe, Oksana; Smith, Gary Scott; Hykin, Philip; Boulton, Michael E.

doi:10.1167/iovs.07-1206

Cited by 143 publications

(125 citation statements)

References 46 publications

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“…Overexpression of Ang1, on the other hand, leads to a stabilized vasculature (39)(40)(41)(42)(43)(44). Also, treatment with recombinant Ang1 has been shown to rescue retinal defects caused by pericyte loss (39,46). Here we report that DA can induce overexpression of Ang1 directly in the pericytes and also can regulate the mobilization and recruitment of these cells, in turn mediating normalization of tumor blood vessels.…”

Section: Discussionmentioning

confidence: 71%

“…In addition, these experiments performed in serum-starved HBVP suggested that the effect of DA on Ang1 expression in pericytes is direct and is not the result of its actions on other growth factors. Furthermore, because there are reports indicating that up-regulation of Ang1 in pericytes stimulates migration of these cells (46,47), we examined the action of DA on HBVP migration (SI Results and Fig. S6).…”

Section: Da Treatment Promotes Mature Pericyte Coverage In Tumor Bloodmentioning

confidence: 99%

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Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells

Chakroborty

Sarkar

et al. 2011

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

100

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Impaired blood flow in the tumor vascular bed caused by structurally and functionally abnormal blood vessels not only hinders the delivery of chemotherapeutic agents but also aggravates tumor hypoxia, making the tumor cells further resistant to antineoplastic drugs. Therefore, normalization of tumor blood vessels may be an important approach to increase therapeutic efficacy in the treatment of cancer patients. As blood vessels are supplied by sympathetic nerves containing dopamine (DA), and DA regulates functions of normal blood vessels through its receptors present in these vessels, we investigated the effect of DA on tumor vasculature. Here we report loss of sympathetic innervation and endogenous DA in abnormal and immature tumor blood vessels in malignant colon and prostate tumor tissues. In contrast, exogenous administration of DA normalizes the morphology and improves the functions of these vessels by acting on pericytes and endothelial cells, the two major cellular components of blood vessels. DA acts through its D 2 receptors present in these cells to up-regulate directly the expression of angiopoietin 1 (Ang1) in pericytes and the expression of the zinc finger transcriptional factor, Krüppel-like factor-2 (KLF2) in tumor endothelial cells. Importantly, this vessel stabilization by DA also significantly increases the concentration of anticancer drug in tumor tissues. These results show a relationship between vascular stabilization and a neurotransmitter and indicate that DA or its D 2 receptor-specific agonists can be an option for the treatment of cancer and disorders in which normalization of blood vessels may have therapeutic benefits.I t now is well established that tumor blood vessels are structurally and functionally abnormal (1-4). In contrast to normal blood vessels, which are well organized and lined by quiescent adult endothelial cells and supporting mature pericytes, tumor vessels are highly disorganized and made up of active endothelial cells (1-6). Moreover, in these tumor vessels pericytes are lacking or immature pericytes attach loosely to the endothelial cells (1-3). This vascular immaturity in turn causes destabilization of vessel structure, impairment of endothelial barrier function, and decreased blood flow leading to increased hypoxia in tumor tissues (1-3). In addition, the impaired blood flow in abnormal tumor blood vessels not only compromises the delivery of anticancer drugs but also aggravates tumor hypoxia, making tumor cells more resistant to these agents (1-3). Thus, stabilization or normalization of tumor vessels can be an important approach to increase the therapeutic efficacy of anticancer drugs (1, 7). Dopamine (DA) is a monoamine catecholamine neurotransmitter, which acts through its D 1 and D 2 class of receptors present in the target organs (8, 9). In addition to its conventional role in the brain, recent reports indicate that DA also controls several functions in the periphery (8, 9). DA has been shown to regulate behavior, movement, and cardiovascular, renal, endocrine...

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Section: Discussionmentioning

confidence: 71%

Section: Da Treatment Promotes Mature Pericyte Coverage In Tumor Bloodmentioning

confidence: 99%

Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells

Chakroborty

Sarkar

et al. 2011

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

100

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“…Other angiogenic factors are the angiopoietin/Tie-2 system which, as mentioned earlier, modulates the effect of VEGF on endothelial cells (Takagi et al 2003;Cai et al 2008). Several cytokines also have been shown to have a role in new vessel formation in PDR such as insulinlike growth factor-1 (IGF-1), interleukin-8, placental growth factor, hepatocyte growth factor, platelet-derived growth factor (PDGF), and leptin (Simo et al 2006).…”

Section: Angiogenic Mechanisms In Proliferative Diabetic Retinopathymentioning

confidence: 98%

“…Both angiopoietins interact with a tyrosine kinase receptor called Tie-2 receptor (Suri et al 1996;Maisonpierre et al 1997). The angiopoietin/Tie-2 system has an important role in the pathogenesis of proliferative diabetic retinopathy (Takagi et al 2003;Cai et al 2008).…”

Section: Key Angiogenic Growth Factors Involved In Proliferative Retimentioning

confidence: 99%

Antiangiogenic Therapy for Ischemic Retinopathies

Al-Latayfeh¹,

Silva²,

Sun³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

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“…In addition, paracrine signalling from ECs recruits pericytes by the secretion of platelet derived growth factor (PDGF)-BB, which binds to the PDGFRβ receptor expressed on pericytes (Bjarnegard et al, 2004). In addition, the secretion of angiopoietin 1 (Ang-1) by pericytes mediates pericyte-endothelial attachment via the Tie2 receptor, which is expressed by ECs (Cai et al, 2008;Sundberg et al, 2002). Disruptions in pericyte-endothelial interactions can result in the loss of pericyte coverage from the vessels and lead to a leaky vasculature, resulting in haemorrhage and oedema (Hellstrom et al, 1999;Soriano, 1994).…”

Section: Bone Marrow-derived Mesenchymal Stem Cells and Pericytes -Dementioning

confidence: 99%

Pericytes, mesenchymal stem cells and their contributions to tissue repair

Wong

Rowley

Redpath

et al. 2015

Pharmacology & Therapeutics

146

110

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Regenerative medicine using mesenchymal stem cells for the purposes of tissue repair has garnered considerable public attention due to the potential of returning tissues and organs to a normal, healthy state after injury or damage has occurred. To achieve this, progenitor cells such as pericytes and bone marrow-derived mesenchymal stem cells can be delivered exogenously, mobilised and recruited from within the body or transplanted in the form organs and tissues grown in the laboratory from stem cells. In this review, we summarise the recent evidence supporting the use of endogenously mobilised stem cell populations to enhance tissue repair along with the use of mesenchymal stem cells and pericytes in the development of engineered tissues. Finally, we conclude with an overview of currently available therapeutic options to manipulate endogenous stem cells to promote tissue repair.

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The Angiopoietin/Tie-2 System Regulates Pericyte Survival and Recruitment in Diabetic Retinopathy

Abstract: These findings demonstrate that Tie-2 is functional in pericytes and may play an important role in the progression of diabetic retinopathy, by regulating pericyte loss and influencing the activation state and recruitment of pericytes.

Cited by 143 publications

References 46 publications

Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells

Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells

Antiangiogenic Therapy for Ischemic Retinopathies

Pericytes, mesenchymal stem cells and their contributions to tissue repair

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