Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice

Zhou, Quan; Guo, Renhua; Wood, Ronald W.; Boyce, Brendan F.; Liang, Qianqian; Wang, Yongjun; Schwarz, Edward M.; Xing, Lianping

doi:10.1002/art.30421

Cited by 114 publications

(113 citation statements)

References 44 publications

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“…Recent studies in animals provide evidence that affecting lymphatic drainage by promoting the growth of lymphatic vessels can modulate inflammation 60, 61, 62, 63. Lymphatic vessel hyperplasia has been associated with hypercholesterolemia,42 but we show here that apoA‐I does not reduce vessel diameters.…”

Section: Discussioncontrasting

confidence: 44%

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Milasan

Jean

Dallaire

et al. 2017

JAHA

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BackgroundSubcutaneously injected lipid‐free apoA‐I (apolipoprotein A‐I) reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without increasing high‐density lipoprotein–cholesterol concentrations. Lymphatic vessels are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and particular attention has been brought to the role of the collecting lymphatic vessels in early atherosclerosis‐related lymphatic dysfunction. In the present study, we address whether and how preservation of collecting lymphatic function contributes to the protective effect of apoA‐I.Methods and ResultsAtherosclerotic Ldlr −/− mice treated with low‐dose lipid‐free apoA‐I showed enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic Ldlr −/− mice when compared with albumin‐control mice. Treatment of human lymphatic endothelial cells with apoA‐I increased the adhesion of human platelets on lymphatic endothelial cells, in a bridge‐like manner, a mechanism that could strengthen endothelial cell–cell junctions and limit atherosclerosis‐associated collecting lymphatic vessel dysfunction. Experiments performed with blood platelets isolated from apoA‐I‐treated Ldlr −/− mice revealed that apoA‐I decreased ex vivo platelet aggregation. This suggests that in vivo apoA‐I treatment limits platelet thrombotic potential in blood while maintaining the platelet activity needed to sustain adequate lymphatic function.ConclusionsAltogether, we bring forward a new pleiotropic role for apoA‐I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis.

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Section: Discussioncontrasting

confidence: 44%

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Milasan

Jean

Dallaire

et al. 2017

JAHA

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“…ApoA-I also reduced TNF-R1 signaling and conserved Prox-1 expression in LECs. These results were further corroborated in hTNFtg mice, 3,6,19 where the phenotype of the lymphatic vasculature of the diaphragm was normalized by apoA-I treatment. This suggests that apoA-I may regulate protective molecular pathways in lymphatic endothelium, and therefore, it is a potential therapeutic target with the capacity to improve lymphatic function and promote resolution of acute and chronic inflammatory states.…”

Section: Discussionsupporting

confidence: 52%

“…24 In addition, hTNFtg mice, a model of chronic inflammatory arthritis, exhibit decreased lymph flow from the joints compared with wild-type littermates. 6 Finally, TNF blockade in patients with rheumatoid arthritis and in experimental arthritis has been shown to promote lymphatic vessel formation and the resolution of chronic synovial inflammation.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis

Bisoendial

Tabet

Tak

et al. 2015

ATVB

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Objective— Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo) A-I, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF. Approach and Results— TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apoA-I attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apoA-I reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. ApoA-I also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. ApoA-I also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice. Conclusions— ApoA-I restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein–based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature.

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“…The studies investigating AAV transduction in injured joints are limited with prior work focused more on rheumatoid arthritis (Pan et al, 1999;Goater et al, 2000;Zhou et al, 2011). Two groups used a transgenic mouse model that spontaneously develops arthritis due to tumor necrosis factor (TNF)-a overexpression (Goater et al, 2000;Zhou et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Two groups used a transgenic mouse model that spontaneously develops arthritis due to tumor necrosis factor (TNF)-a overexpression (Goater et al, 2000;Zhou et al, 2011). Goater et al (2000) reported increased AAV transduction efficiency with increased degree of the joint disease following an intra-articular injection of AAV, with synoviocytes as the primary target.…”

Section: Discussionmentioning

confidence: 99%

Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

et al. 2013

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A single intra-articular injection of adeno-associated virus (AAV) results in stable and controllable transgene expression in normal rat knees. Because undamaged joints are unlikely to require treatment, the study of AAV delivery in joint injury models is crucial to potential therapeutic applications. This study tests the hypotheses that persistent and controllable AAV-transgene expression are (1) highly localized to the cartilage when AAV is injected postinjury and (2) localized to the intra-articular soft tissues when AAV is injected preinjury. Two AAV injection time points, postinjury and preinjury, were investigated in osteochondral defect and anterior cruciate ligament transection models of joint injury. Rats injected with AAV tetracycline response element (TRE)-luciferase received oral doxycycline for 7 days. Luciferase expression was evaluated longitudinally for 6 months. Transgene expression was persistent and controllable with oral doxycycline for 6 months in all groups. However, the location of transgene expression was different: postinjury AAV-injected knees had luciferase expression highly localized to the cartilage, while preinjury AAV-injected knees had more widespread signal from intraarticular soft tissues. The differential transgene localization between preinjury and postinjury injection can be used to optimize treatment strategies. Highly localized postinjury injection appears advantageous for treatments targeting repair cells. The more generalized and controllable reservoir of transgene expression following AAV injection before anterior cruciate ligament transection (ACLT) suggests an intriguing concept for prophylactic delivery of joint protective factors to individuals at high risk for early osteoarthritis (OA). Successful external control of intra-articular transgene expression provides an added margin of safety for these potential clinical applications.

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Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice

Cited by 114 publications

References 44 publications

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis

Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

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