Midkine acts as proangiogenic cytokine in hypoxia-induced angiogenesis (original) (raw)
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Circulation, 2006
Background— Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, eg, neural survival, carcinogenesis, and tissue repair. MK could have a protective action against ischemia/reperfusion (I/R) injury in the heart, because MK was shown to have cytoprotective activity in cultured neurons and tumor cells. We investigated this hypothesis in mice with and without genetic MK deletion. Methods and Results— Myocardial injury after I/R was produced by transient occlusion of coronary arteries. In wild-type ( Mdk +/+ ) mice, MK expression was increased after I/R in the periinfarct area. Infarct size/area at risk 24 hours after I/R in MK-deficient ( Mdk −/− ) mice was larger than in Mdk +/+ mice (55.4±9.1% versus 32.1±5.3%, P <0.05). Terminal dUTP nick end-labeling–positive myocyte population in the periinfarct area in Mdk −/− mice was higher than in Mdk +/+ mice (6.8±0.9% versus 3.2±0.6%, P <0.05). Left ventricular fractional shortening 24 hours after I/...
The American Journal of Pathology, 2000
The ␣61 integrin has been implicated in breast carcinoma progression, but the mechanisms involved remain elusive. MDA-MB-435 cells engineered to be deficient in ␣61 expression form primary tumors that are highly apoptotic and unable to metastasize, although they exhibit no increased apoptosis in vitro under standard culture conditions. Based on the hypothesis that ␣61 is necessary for the survival of these cells in the tumor microenvironment, we report here that hypoxia protects these cells from apoptosis induced by serum deprivation and that hypoxia-mediated protection requires ␣61 expression. We investigated the influence of ␣61 on vascular endothelial growth factor (VEGF) expression because autocrine VEGF is necessary for the survival of serum-deprived cells in hypoxia. The results obtained indicate that ␣61 is necessary for VEGF expression because the ability of hypoxia to activate HIF-1 and to stimulate VEGF transcription in MDA-MB-435 cells is dependent on ␣61 expression by a mechanism that involves protein kinase C-␣.
Therapeutic potential of midkine in cardiovascular disease
British Journal of Pharmacology, 2014
Ischaemic heart disease, stroke and their pathological consequences are life-threatening conditions that account for about half of deaths in developed countries. Pathology of these diseases includes cell death due to ischaemia/reperfusion injury, vascular stenosis and cardiac remodelling. The growth factor midkine plays a pivotal role in these events. Midkine shows an acute cytoprotective effect in ischaemia/reperfusion injury at least in part via its anti-apoptotic effect. Moreover, while midkine promotes endothelial cell proliferation, it also recruits inflammatory cells to lesions. These activities eventually enhance angiogenesis, thereby preventing cardiac tissue remodelling. However, midkine's activity in recruiting inflammatory cells into the vascular wall also triggers neointima formation, and consequently, vascular stenosis. Moreover, midkine is induced in cancer tissues where it enhances angiogenesis. Therefore, midkine may promote tumour formation through its angiogenic and anti-apoptotic activity. This review focuses on the roles of midkine in ischaemic cardiovascular disease and their pathological consequences, that is angiogenesis, vascular stenosis, and cardiac remodelling, and discusses the possible therapeutic potential of modulation of midkine in these diseases.
Midkine in Inflammatory and Toxic Conditions
Current Drug Delivery, 2013
Midkine (MK) is a member of midkine family which is composed of MK and pleotrophin (PTN). MK behaves like a cytokine and growth factor, promotes the proliferation, differentiation, survival, adhesion, migration of cells. MK expression usually increases during ischemia, inflammation, tissue repair, neoplastic transformation and in different toxic conditions. Immune cells and most of organs have MK secretion function in fetal and adult life. MK could be a promising prognostic/diagnostic marker and a potential target in many of diseases including malignancy, toxic and inflammatory diseases. This review focuses on both cell protective and immune-modulatory roles of MK in different in vitro and in vivo disease models and human reports. MK is still a novel molecule in the regulation of organ development and the etiology of many diseases.
Endothelial Cells as Tools to Model Tissue Microenvironment in Hypoxia-Dependent Pathologies
International Journal of Molecular Sciences
Endothelial cells (ECs) lining the blood vessels are important players in many biological phenomena but are crucial in hypoxia-dependent diseases where their deregulation contributes to pathology. On the other hand, processes mediated by ECs, such as angiogenesis, vessel permeability, interactions with cells and factors circulating in the blood, maintain homeostasis of the organism. Understanding the diversity and heterogeneity of ECs in different tissues and during various biological processes is crucial in biomedical research to properly develop our knowledge on many diseases, including cancer. Here, we review the most important aspects related to ECs’ heterogeneity and list the available in vitro tools to study different angiogenesis-related pathologies. We focus on the relationship between functions of ECs and their organo-specificity but also point to how the microenvironment, mainly hypoxia, shapes their activity. We believe that taking into account the specific features of EC...
Life Sciences, 2012
Aims: Lymphangiogenesis refers to the formation of new lymphatic vessels and is thought to constitute conduits for the tumor cells to metastasize. We previously demonstrated that endothelin (ET)-1 through its binding with ETB receptor (ET B R) expressed on lymphatic endothelial cells (LEC), induced cell growth and invasiveness. Since vascular endothelial growth factor (VEGF)-A/-C/-D, and hypoxia play key role in lymphatic differentiation, in this study we investigated the involvement of these growth factors and hypoxia in ET-1-induced lymphangiogenesis. Main methods: Real time PCR and ELISA were used to quantify VEGF-A/-C/-D. LEC morphological differentiation was analyzed by tube formation assay on Matrigel. Key findings: Hypoxia, as well as ET-1, induced an increase in VEGF-A/-C and-D expression that was reduced in the presence of a selective ET B R antagonist, BQ788, and enhanced when ET-1 was administered under hypoxic conditions. We analyzed the role of hypoxia on LEC morphological differentiation, and found that hypoxia increased the formation of vascular-like structures on Matrigel and that in combination with ET-1 this effect was markedly enhanced. The use of specific antibodies neutralizing VEGF-A, or recombinant VEGFR-3/(Flt-4)/ Fc that block VEGF-C/-D, inhibited the effect of ET-1 as well that of hypoxia. Significance: These results demonstrated that ET-1 and hypoxia act, at list in part, through VEGF to induce lymphangiogenic events and that these two stimuli may cooperate to induce VEGF-A/-C/-D expression and lymphatic differentiation. These data further support the role of ET-1 as potent lymphangiogenic factor that relies on the interplay with hypoxic microenvironment and with VEGF family members.
Stroke, 2003
Background and Purpose-Endoglin (CD105) is a membrane glycoprotein that is mutated in hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) and shows increased expression in proliferating endothelial cells during angiogenesis. Methods-We investigated the effect of hypoxia on endoglin expression in murine cerebral microvascular endothelial (bEND.3) cells in vitro and the possible involvement of mitogen-activated protein kinase (MAPK) pathways. Results-Hypoxia increased endoglin mRNA and protein expression in bEND.3 cells, which was associated with phosphoactivation of extracellular signal-related kinase (ERK), p38 MAPK, and Jun amino-terminal kinase (JNK). Inhibitors of p38 decreased hypoxic induction of endoglin expression, as did dominant negative MAPK kinase 3 (MKK3), which activates p38. In contrast, constitutively active MKK3 or JNK1 potentiated the hypoxic induction of endoglin. Conclusions-These results indicate that hypoxia induces the expression of endoglin at both the mRNA and protein levels and that induction is regulated by the p38 and perhaps also JNK pathways. (Stroke. 2003;34:2483-2488.) Key Words: angiogenesis Ⅲ brain Ⅲ endoglin Ⅲ endothelium Ⅲ hypoxia Ⅲ mitogen-activated protein kinases Ⅲ protein kinases
Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells
Ischemia-induced apoptosis of endothelial cells may contribute to tissue injury, organ failure, and transplantation rejection. However, little is known about survival mechanisms capable to counteract endothelial apoptosis. This study investigated the potential role of an endogenous anti-apoptotic response elicited by transient hypoxia, capable to avert ongoing apoptosis in endothelial cells. Experiments were carried out in three different types of cultured endothelial cells (human umbilical vein, pig aorta, and from rat coronary microvasculature). As a pro-apoptotic challenge endothelial cells were cultured in serum-free medium and subjected to hypoxia for 2 h. We found that transient hypoxia reduced caspase 3 activation within 1 h of hypoxia. Accordingly, the number of apoptotic cells was reduced after 24 h of reoxygenation. This was true for all three cell types analyzed. Analysis of Akt and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) ...
Wound repair and tumor vascularization depend upon blood vessel growth into hypoxic tissue. Although hypoxia slows endothelial cell (EC) proliferation and suppresses EC basic fibroblast growth factor (bFGF) expression , we report that macrophages (MPs) exposed to Po2 12-14 torr (1 torr = 1333 Pa) synthesize and release in a time-dependent manner platelet-derived growth factor (PDGF) and acidic/basic FGFs (a/bFGFs), which stimulate the growth of hypoxic ECs. Chromatography of hypoxic MP-conditioned medium on immobilized heparin with an ascending NaCl gradient resolved three peaks of mitogenic activity: activity of the first peak was neutralized by antibody to PDGF; activity of the second peak was neutralized by antibody to aFGF; and activity of the third peak was neutralized by antibody to bFGF. Metabolically labeled lysates and supernatants from MPs exposed to hypoxia showed increased synthesis and release of immunoprecipitable PDGF and a/bFGF in the absence of changes in cell viability. Possible involvement of a heme-containing oxygen sensor in MP elaboration of growth factors was suggested by the induction of bFGF and PDGF by normoxic MPs exposed to nickel or cobalt, although metabolic inhibitors such as sodium azide were without effect. These results suggest a paracrine model in which hypoxia stimulates MP release of PDGF and a/bFGF, inducing EC proliferation and potentially promoting angiogenesis in hypoxic environments.