Rivaroxaban, a factor Xa inhibitor, improves neovascularization in the ischemic hindlimb of streptozotocin-induced diabetic mice

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Abstract

Background

Factor Xa inhibitor is used for preventing venous thromboembolism (VTE) in adult patients receiving orthopedic operation. However, the role of factor Xa inhibitor, rivaroxaban, in angiogenesis is still unknown.

Methods and results

Streptozotocin (STZ)–induced diabetic mice with model of hind-limb ischemia, were divided into non-diabetic control, diabetic control, and low- and high-dose rivaroxaban treatment groups, in order to evaluate the effect of rivaroxaban in angiogenesis. Doppler perfusion imaging showed that blood flow recovery was significantly increased, and more capillary density occurred in the rivaroxaban treatment group. In vitro studies, human endothelial progenitor cells (EPCs) treated with rivaroxaban had significant functional improvement in migration and senescence under hyperglycemic conditions. Rivaroxaban also increased endothelial nitric oxide synthase (eNOS) as well as vascular endothelial growth factor (VEGF) expressions in hyperglycemia-stimulated EPCs.

Conclusions

Rivaroxaban promoted vessel formation in diabetic mice and improved endothelial progenitor cell function under hyperglycemic conditions. These effects may be associated with enhancement of expression of eNOS and VEGF.

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Most cited references 28

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Rivaroxaban in patients with a recent acute coronary syndrome.

Jessica Mega, Eugene Braunwald, Stephen Wiviott … (2012)

Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

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Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing.

Kazuichi Maruyama, Tina Thorne, Douglas W. Losordo … (2007)

Impaired wound healing is a common complication of diabetes. Although it is well known that both macrophages and blood vessels are critical to wound repair, the role of wound-associated lymphatic vessels has not been well investigated. We report that both the presence of activated macrophages and the formation of lymphatic vessels are rate-limiting to the healing of diabetic wounds. We have previously shown that macrophages contribute to the lymphatic vessels that form during the acute phase of corneal wound healing. We now demonstrate that this is a general phenomenon; cells that co-stain for the macrophage marker F4/80 and the lymphatic markers LYVE-1 (lymphatic vascular endothelium hyaluronate receptor) and podoplanin contribute to lymphatic vessels in full-thickness wounds. LYVE-1-positive lymphatic vessels and CD31-positive blood vessels were significantly reduced in corneal wound healing in diabetic mice (db/db) (P < 0.02) compared with control (db/+) mice. Glucose treatment of control macrophages led to the down-regulation of the lymphatic-specific receptor VEGFR3 and its ligands, vascular endothelial growth factor-C and -D (VEGF-C, -D). Interleukin-1beta stimulation rescued diabetic macrophage function; application of interleukin-1beta-treated db/db-derived macrophages to wounds in db/db mice induced lymphatic vessel formation and accelerated wound healing. These observations suggest a potential therapeutic approach for healing wounds in diabetic patients.

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Abnormal angiogenesis in diabetes mellitus.

David C. Sane, Michael R Komada, Alexandra Côté-Martin (2003)

The adverse long-term effects of diabetes mellitus have been well described and involve many organ systems. While diabetes management has largely focused on control of hyperglycemia, the presence of abnormalities of angiogenesis may cause or contribute to many of the clinical manifestations of diabetes. When compared with non-diabetic subjects, diabetics demonstrate vascular abnormalities of the retina, kidneys, and fetus. Diabetics have impaired wound healing, increased risk of rejection of transplanted organs, and impaired formation of coronary collaterals. In each of these conditions, and possibly in diabetic neuropathy as well, abnormalities of angiogenesis can be implicated in the pathogenesis. A perplexing feature of the aberrant angiogenesis is that excessive and insufficient angiogenesis can occur in different organs in the same individual. In this review, the clinical features, molecular mechanisms, and potential therapeutic options of abnormal angiogenesis in diabetes will be reviewed. Copyright 2002 Wiley Periodicals, Inc.

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Author and article information

Contributors

Jaw-Wen Chen: jwchen@vghtpe.gov.tw

Journal

Journal ID (nlm-ta): Cardiovasc Diabetol

Journal ID (iso-abbrev): Cardiovasc Diabetol

Title: Cardiovascular Diabetology

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2840

Publication date (Electronic): 16 June 2015

Publication date PMC-release: 16 June 2015

Publication date Collection: 2015

Volume: 14

Electronic Location Identifier: 81

Affiliations

[ ]Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

[ ]Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan

[ ]Renal Division, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan County, Taiwan

[ ]Division of Cardiovascular Surgery, Department of Surgery, Healthcare and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan

[ ]Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

[ ]Department of Medical Research and Education, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan ROC

[ ]Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan

Article

Publisher ID: 243

DOI: 10.1186/s12933-015-0243-y

PMC ID: 4473833

PubMed ID: 26077117

SO-VID: 3eaacdad-fb0c-4392-932a-4526d1ec399c

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 March 2015

Date accepted : 6 June 2015

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: factor xa inhibitor,diabetes,angiogenesis,endothelial progenitor cells

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: factor xa inhibitor, diabetes, angiogenesis, endothelial progenitor cells

Rivaroxaban, a factor Xa inhibitor, improves neovascularization in the ischemic hindlimb of streptozotocin-induced diabetic mice

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Abstract

Background

Methods and results

Conclusions

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Bioscientifica Open Endocrinology

Most cited references 28

Rivaroxaban in patients with a recent acute coronary syndrome.

Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing.

Abnormal angiogenesis in diabetes mellitus.

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