Three-dimensional morphologic and molecular atlases of nasal vasculature

Hong, Seon Pyo; Yang, Myung Jin; Bae, Jung Hyun; Choi, Du Ri; Kim, Young-Chan; Yang, Myeon‐Sik; Oh, Byungkwan; Kang, Kyung‐Won; Lee, Sang-Myeong; Kim, Bumseok; Kim, Yong‐Dae; Ahn, Ji Hoon; Koh, Gou Young

doi:10.1038/s44161-023-00257-3

Cited by 3 publications

(1 citation statement)

References 61 publications

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“…Lymphatics are abundant in all regions of the upper respiratory tract, including the nose, nasopharynx and trachea 45,46 . They are also abundant in the hard and soft palates and other parts of the oral cavity.…”

Section: Articlementioning

confidence: 99%

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage

Yoon,

Jin,

Kim

et al. 2024

Nature

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Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1–17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.

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Section: Articlementioning

confidence: 99%

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage

Yoon,

Jin,

Kim

et al. 2024

Nature

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A systems view of the vascular endothelium in health and disease

Augustin,

Koh

2024

Cell

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Arterial endothelial deletion of hereditary hemorrhagic telangiectasia 2/Alk1causes epistaxis and cerebral microhemorrhage with aberrant arteries and defective smooth muscle coverage

Zhang,

Jacobs,

Raygor

et al. 2024

Preprint

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Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder with presentations including severe nose bleeding and microhemorrhage in brains. Despite being the second most common inherited bleeding disorder, the pathophysiological mechanism underlying HHT-associated hemorrhage is poorly understood. Mutations in activin receptor-like kinase 1 (ALK1) gene cause HHT type 2. HHT pathogenesis is thought to follow a Knudsonian two-hit model, requiring a second somatic mutation for lesion formation. We hypothesize that somatic mutation ofAlk1in arterial endothelial cells (AECs) leads to arterial defects and hemorrhage. Here, we investigate the effects of Alk1 mutation in AECs in mice, usingBmx(PAC)-CreERT2-mediated postnatal somatic mutation. We mutatedAlk1in primarily AECs and found that somatic arterial endothelial mutation ofAlk1is sufficient to induce spontaneous epistaxis and multifocal cerebral microhemorrhage. Interestingly, this bleeding occurred in the presence of tortuous and enlarged blood vessels, loss of arterial molecular markerEfnb2, disorganization of vascular smooth muscle, and impaired vasoregulation. Our data suggest that arterial endothelial mutation ofAlk1causing reduced arterial identity and disruption of vascular smooth muscle cell coverage is a plausible molecular mechanism for HHT-associated severe epistaxis. This work provides the first evidence that somatic ALK1 loss in AECs can cause hemorrhagic vascular lesions, offering a novel preclinical model critically needed for studying HHT-associated epistaxis, and delineating an arterial mechanism to HHT pathophysiology.

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Three-dimensional morphologic and molecular atlases of nasal vasculature

Cited by 3 publications

References 61 publications

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage

A systems view of the vascular endothelium in health and disease

Arterial endothelial deletion of hereditary hemorrhagic telangiectasia 2/Alk1causes epistaxis and cerebral microhemorrhage with aberrant arteries and defective smooth muscle coverage

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