Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels

Vries, Margreet R. de; Parma, Laura; Peters, H.A.B.; Schepers, Abbey; Hamming, Jaap F.; Jukema, J. Wouter; Goumans, Marie–José; Guo, Liang; Finn, Aloke V.; Virmani, Renu; Ozaki, C. Keith; Quax, Paul H.A.

doi:10.1111/joim.12821

Cited by 45 publications

(59 citation statements)

References 44 publications

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“…This likely occurred by enhancing the maturation of newly developed VV primarily in the adventitia. 55 Coronary arteries of hypercholesterolemic pigs show that the adventitial VV begins to proliferate before aortic wall thickening and that the proliferation is, in turn, preceded by infiltration of inflammatory cells into the adventitia, which release, for example, VEGF-A, promoting the growth of new VV. 56 These new capillaries, often leaky and poorly organized, can lead to small hemorrhages in a growing atherosclerotic lesion and may rupture from within, generating vulnerable plaques, which, in turn, may promote fibrous cap rupture.…”

Section: Adventitial Vv In Diseasementioning

confidence: 99%

Recent Developments in Vascular Adventitial Pathobiology

Tinajero

Gotlieb

2020

The American Journal of Pathology

100

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The adventitia, the outer layer of the blood vessel wall, may be the most complex layer of the wall and may be the master regulator of wall physiology and pathobiology. This review proposes a major shift in thinking to apply a functional lens to the adventitia rather than only a structural lens. Human and experimental in vivo and in vitro studies show that the adventitia is a dynamic microenvironment in which adventitial and perivascular adipose tissue cells initiate and regulate important vascular functions in disease, especially intimal hyperplasia and atherosclerosis. Although well away from the bloodwall interface, where much pathology has been identified, the adventitia has a profound influence on the population of intimal and medial endothelial, macrophage, and smooth muscle cell function. Vascular injury and dysfunction of the perivascular adipose tissue promote expansion of the vasa vasorum, activation of fibroblasts, and differentiation of myofibroblasts. This regulates further biologic processes, including fibroblast and myofibroblast migration and proliferation, inflammation, immunity, stem cell activation and regulation, extracellular matrix remodeling, and angiogenesis. A debate exists as to whether the adventitia initiates disease or is just an important participant. We describe a mechanistic model of adventitial function that brings together current knowledge and guides the design of future investigations to test specific hypotheses on adventitial pathobiology.

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Section: Adventitial Vv In Diseasementioning

confidence: 99%

Recent Developments in Vascular Adventitial Pathobiology

Tinajero

Gotlieb

2020

The American Journal of Pathology

100

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“…In fact, differently from Marsch et al, who treated mice daily for five days, followed by two days of no carbogen exposure we performed the treatment daily and started our treatment seven days after mice underwent vein graft of 18 surgery, when the atherosclerotic lesions already started forming. This starting time point was based on our previous findings [5] in which we found that intraplaque neovascularization in ApoE3*Leiden mice that underwent vein graft surgery is visible 14 days after surgery. Therefore, we were able to study the effect of carbogen treatment on lesion stabilization rather than on lesion formation.…”

Section: Discussionmentioning

confidence: 99%

“…Vein graft surgery was performed by donor mice caval vein interpositioning in the carotid artery of recipient mice as previously described [5,18]. Briefly, thoracic caval veins from donor mice were harvested.…”

Section: Vein Graft Surgerymentioning

confidence: 99%

“…Chronic reoxygenation was investigated in ApoE3*Leiden mice starting on day 7 after vein graft surgery. The decision for this timepoint was based on our previous finding that intraplaque angiogenesis is detectable in ApoE3*Leiden mice starting from day 14 after vein graft surgery [5]. Mice were randomized based on their plasma cholesterol levels (Roche Diagnostics, kit 1489437, Basel, Switzerland) and body weight in two groups, a control group (n = 16) and a carbogen treated group (n = 16) and exposed daily for 90 min to air (21% O 2 ) or carbogen (95% O 2 , 5% CO 2 ) respectively, until the day of sacrifice.…”

Section: Carbogen Treatmentmentioning

confidence: 99%

“…Lack of oxygen within the plaque, or intraplaque hypoxia, has been identified as one of the major contributors to plaque instability [2,3]. It has been detected in advanced human atherosclerotic lesions [4] as well as in murine atherosclerotic lesions [5,6].…”

Section: Introductionmentioning

confidence: 99%

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Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3*Leiden Mice

Parma

Peters

Baganha

et al. 2020

Cells

Self Cite

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Unstable atherosclerotic plaques frequently show plaque angiogenesis which increases the chance of rupture and thrombus formation leading to infarctions. Hypoxia plays a role in angiogenesis and inflammation, two processes involved in the pathogenesis of atherosclerosis. We aim to study the effect of resolution of hypoxia using carbogen gas (95% O2, 5% CO2) on the remodeling of vein graft accelerated atherosclerotic lesions in ApoE3*Leiden mice which harbor plaque angiogenesis. Single treatment resulted in a drastic decrease of intraplaque hypoxia, without affecting plaque composition. Daily treatment for three weeks resulted in 34.5% increase in vein graft patency and increased lumen size. However, after three weeks intraplaque hypoxia was comparable to the controls, as were the number of neovessels and the degree of intraplaque hemorrhage. To our surprise we found that three weeks of treatment triggered ROS accumulation and subsequent Hif1a induction, paralleled with a reduction in the macrophage content, pointing to an increase in lesion stability. Similar to what we observed in vivo, in vitro induction of ROS in bone marrow derived macrophages lead to increased Hif1a expression and extensive DNA damage and apoptosis. Our study demonstrates that carbogen treatment did improve vein graft patency and plaque stability and reduced intraplaque macrophage accumulation via ROS mediated DNA damage and apoptosis but failed to have long term effects on hypoxia and intraplaque angiogenesis.

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Low‐Intensity Focused Ultrasound‐Responsive Ferrite‐Encapsulated Nanoparticles for Atherosclerotic Plaque Neovascularization Theranostics

et al. 2021

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Pathological angiogenesis is a crucial factor that causes atherosclerotic plaque rupture. Sinoporphyrin sodium-mediated sonodynamic therapy (DVDMS-SDT) induces regression of plaque neovascularization in humans without causing obvious side effects. However, a clinical noninvasive theranostic strategy for atherosclerotic plaque neovascularization is urgently needed. A nanoplatform designed for multimodality imaging-guided SDT in plaque angiogenesis theranostics, termed PFP-HMME@PLGA/ MnFe 2 O 4 -ramucirumab nanoparticles (PHPMR NPs), is fabricated. It encapsulates manganese ferrite (MnFe 2 O 4 ), hematoporphyrin monomethyl ether (HMME), and perfluoropentane (PFP) stabilized by polylactic acid-glycolic acid (PLGA) shells and is conjugated to an anti-VEGFR-2 antibody. With excellent magnetic resonance imaging (MRI)/photoacoustic/ ultrasound imaging ability, the distribution of PHPMR NPs in plaque can be observed in real time. Additionally, they actively accumulate in the mitochondria of rabbit aortic endothelial cells (RAECs), and the PHPMR NP-mediated SDT promotes mitochondrial-caspase apoptosis via the production of reactive oxygen species and inhibits the proliferation, migration, and tubulogenesis of RAECs. On day 3, PHPMR NP-mediated SDT induces apoptosis in neovessel endothelial cells and improves hypoxia in the rabbit advanced plaque. On day 28, PHPMR NP-mediated SDT reduces the density of neovessels, subsequently inhibiting intraplaque hemorrhage and inflammation and eventually stabilizing the plaque. Collectively, PHPMR NP-mediated SDT presents a safe and effective theranostic strategy for inhibiting plaque angiogenesis.

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Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels

Abstract: Inhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.

Cited by 45 publications

References 44 publications

Recent Developments in Vascular Adventitial Pathobiology

Recent Developments in Vascular Adventitial Pathobiology

Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3*Leiden Mice

Low‐Intensity Focused Ultrasound‐Responsive Ferrite‐Encapsulated Nanoparticles for Atherosclerotic Plaque Neovascularization Theranostics

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