Effects of LDL Receptor Modulation on Lymphatic Function

Milasan, Andreea; Dallaire, François; Mayer, Gaétan; Martel, Catherine

doi:10.1038/srep27862

Cited by 41 publications

(68 citation statements)

References 64 publications

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“…This concurs with previous findings showing progression stage dependent increases in lymphatic capillary content in human carotid artery plaque1920, and with the recent observation that lymphatic dysfunction precedes the onset of atherosclerosis30. Interestingly, inhibition of VEGFC/D dependent lymphangiogenesis did, in contrast to lymph node/efferent dissection, not affect the atherosclerotic burden, while increasing adventitial and plaque CD3 + T cell content.…”

Section: Discussionsupporting

confidence: 93%

Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis

Rademakers

Vorst

Daissormont

et al. 2017

Sci Rep

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During plaque progression, inflammatory cells progressively accumulate in the adventitia, paralleled by an increased presence of leaky vasa vasorum. We here show that next to vasa vasorum, also the adventitial lymphatic capillary bed is expanding during plaque development in humans and mouse models of atherosclerosis. Furthermore, we investigated the role of lymphatics in atherosclerosis progression. Dissection of plaque draining lymph node and lymphatic vessel in atherosclerotic ApoE−/− mice aggravated plaque formation, which was accompanied by increased intimal and adventitial CD3+ T cell numbers. Likewise, inhibition of VEGF-C/D dependent lymphangiogenesis by AAV aided gene transfer of hVEGFR3-Ig fusion protein resulted in CD3+ T cell enrichment in plaque intima and adventitia. hVEGFR3-Ig gene transfer did not compromise adventitial lymphatic density, pointing to VEGF-C/D independent lymphangiogenesis. We were able to identify the CXCL12/CXCR4 axis, which has previously been shown to indirectly activate VEGFR3, as a likely pathway, in that its focal silencing attenuated lymphangiogenesis and augmented T cell presence. Taken together, our study not only shows profound, partly CXCL12/CXCR4 mediated, expansion of lymph capillaries in the adventitia of atherosclerotic plaque in humans and mice, but also is the first to attribute an important role of lymphatics in plaque T cell accumulation and development.

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Section: Discussionsupporting

confidence: 93%

Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis

Rademakers

Vorst

Daissormont

et al. 2017

Sci Rep

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“…We have recently demonstrated that lymphatic dysfunction, at least in an early stage of atherosclerotic disease, is mainly caused by collecting lymphatic vessel impairment 24. In our current experimental design, as the atherosclerotic plaque is already advanced, we do not exclude the fact that the defect in lymphatic transport could now reside in both the initial and the collecting lymphatic vessels.…”

Section: Resultsmentioning

confidence: 88%

“…Therefore, it is very likely that LEC and platelet signaling pathways depend on the amount of cholesterol in their microdomains, consequently modulating platelet aggregation and adhesion to the lymphatic endothelium. As we hypothesize that apoA‐I plays a positive role in preserving lymphatic transport, the expected repercussion would be observable, primarily, at the level of the collecting lymphatic vessel, the entity that is first defective during atherosclerosis‐associated lymphatic dysfunction 24. By improving lymphatic vessel integrity, we believe that apoA‐I would improve lymph transport per se, thus promoting the movement of lymph content toward the blood circulation.…”

Section: Discussionmentioning

confidence: 92%

“…Altogether, these observations point out that more numerous initial lymphatic vessels do not necessarily reflect better functioning lymphatic vessels in our atherosclerotic mouse model. We have recently reported that lymphatic dysfunction associated with the early stage of atherosclerosis appears to be first and foremost linked to a defect in the collecting lymphatic vessel per se 24. Aging64 and chronic HFD65 have also both been associated with a defect in the collecting lymphatic vessels as well, stressing the importance of targeting this portion of the vessel in chronic inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] The concept that lymphatic vessels could influence atherogenesis and lipoprotein transport has first been brought forward several decades ago. [20][21][22] However, we had to wait until recently to directly associate the lymphatic system with atherosclerosis, [23][24][25][26][27] a disease driven by the accumulation of cholesterol in the artery wall, primarily by low-density lipoprotein, leading to increased plaque buildup. 28 It has been described that without a functional lymphatic network, cholesterol excreted from plaque macrophages cannot be properly conducted out of the artery wall, and thus cannot be evacuated.…”

mentioning

confidence: 99%

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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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Microfluidic‐Based Reconstitution of Functional Lymphatic Microvasculature: Elucidating the Role of Lymphatics in Health and Disease

Serrano,

Gillrie,

et al. 2023

Advanced Science

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The knowledge of the blood microvasculature and its functional role in health and disease has grown significantly attributable to decades of research and numerous advances in cell biology and tissue engineering; however, the lymphatics (the secondary vascular system) has not garnered similar attention, in part due to a lack of relevant in vitro models that mimic its pathophysiological functions. Here, a microfluidic‐based approach is adopted to achieve precise control over the biological transport of growth factors and interstitial flow that drive the in vivo growth of lymphatic capillaries (lymphangiogenesis). The engineered on‐chip lymphatics with in vivo‐like morphology exhibit tissue‐scale functionality with drainage rates of interstitial proteins and molecules comparable to in vivo standards. Computational and scaling analyses of the underlying transport phenomena elucidate the critical role of the three‐dimensional geometry and lymphatic endothelium in recapitulating physiological drainage. Finally, the engineered on‐chip lymphatics enabled studies of lymphatic‐immune interactions that revealed inflammation‐driven responses by the lymphatics to recruit immune cells via chemotactic signals similar to in vivo, pathological events. This on‐chip lymphatics platform permits the interrogation of various lymphatic biological functions, as well as screening of lymphatic‐based therapies such as interstitial absorption of protein therapeutics and lymphatic immunomodulation for cancer therapy.

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Effects of LDL Receptor Modulation on Lymphatic Function

Cited by 41 publications

References 64 publications

Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis

Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis

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

Microfluidic‐Based Reconstitution of Functional Lymphatic Microvasculature: Elucidating the Role of Lymphatics in Health and Disease

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