Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis

Yang, Jae‐Ho; Park, Chan Soon; Kim, Soo Hyun; Noh, Tae Wook; Kim, Ju-Hee; Park, Seongyeol; Lee, Jingu; Park, Jang Ryul; Yoo, Dohyun; Jung, Hyun Ho; Takase, Hiroshi; Shima, David T.; Schwaninger, Markus; Lee, Seung-Joo; Kim, Il-Kug; Lee, Junyeop; Ji, Yong‐Sok; Jon, Sangyong; Oh, Wang‐Yuhl; Kim, Pilhan; Ju, Young Seok; Kim, Injune

doi:10.1161/circresaha.119.316476

Cited by 37 publications

(34 citation statements)

References 89 publications

(29 reference statements)

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“… 35 , 36 Systemically, activated RAS is known to increase vascular endothelial permeability in the lung as well as in the CNS via down-regulation of Dll4-Notch signaling; this may exacerbate pulmonary dysfunction, thereby increasing mortality and worsening phenotype in COVID-19 patients. 37 Therefore, associations between impaired RAS, downregulation of ACE2, and advanced stage AMD may partly explain the vulnerability to COVID-19 observed in patients with exudative AMD.…”

Section: Discussionmentioning

confidence: 99%

COVID-19 Morbidity and Severity in Patients With Age-Related Macular Degeneration: A Korean Nationwide Cohort Study

Yang

Moon

Lee

et al. 2022

American Journal of Ophthalmology

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Objective To determine the potential association of age-related macular degeneration (AMD), a representative chronic age-related degenerative disease of the retina associated with inflammation and aging, with susceptibility to SARS-CoV-2 infection and severe COVID-19 outcomes. Design Nationwide cohort study with propensity-score matching. Setting Population-based nationwide cohort in Korea. Study population Data were obtained from the Health Insurance Review & Assessment Service of Korea, including all patients older than 40 years who underwent SARS-CoV-2 testing in South Korea between January 1, 2020, and May 15, 2020 (excluding self-referral). Main outcome measures SARS-CoV-2 test positivity was the primary outcome and severe clinical outcome of COVID-19 was the secondary outcome. Results The unmatched cohort consisted of 135,435 patients who were tested for SARS-CoV-2; 4531 (3.3%) tested positive for SARS-CoV-2; 5493 (4.1%) patients had AMD. After propensity score matching, exudative AMD was associated with an increased likelihood of susceptibility to SARS-CoV-2 infection (adjusted odds ratio [aOR], 1.50; 95% confidence interval [CI], 1.03-2.25), and a considerably greater risk of severe clinical outcomes of COVID-19 (aOR, 2.26; 95% CI, 1.02 to 5.26), but not any AMD and non-exudative AMD. Conclusions In a Korean nationwide cohort, our data suggest that clinicians should be aware of the greater risk of susceptibility to severe clinical outcomes of COVID-19 in patients with exudative AMD. Our findings provide an improved understanding of the relationship between the pathogenesis of COVID-19 and chronic neurological disorders.

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Section: Discussionmentioning

confidence: 99%

COVID-19 Morbidity and Severity in Patients With Age-Related Macular Degeneration: A Korean Nationwide Cohort Study

Yang

Moon

Lee

et al. 2022

American Journal of Ophthalmology

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“…Recent studies in naïve pluripotent embryonic stem cells showed that Netrin1 binding to Unc5B induced FAK-mediated phosphorylation of GSK3α/β, a kinase implicated in LRP6 activation 38 , suggesting one possible mechanism. Finally, because Unc5B is expressed in arterial and capillary endothelium, but not in veins, it is likely to confer BBB integrity in a vessel-segment specific manner, underscoring heterogeneity of BBB regulation in different vascular segments 39 .…”

Section: Discussionmentioning

confidence: 99%

Endothelial Unc5B controls blood-brain barrier integrity

Boyé

Geraldo

Furtado

et al. 2021

Preprint

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Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we showed that the endothelial Netrin1 receptor Unc5B controls BBB integrity by maintaining Wnt/β-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice led to region and size-selective BBB opening. Loss of Unc5B decreased BBB Wnt/β-catenin signaling, and β-catenin overexpression rescued Unc5B mutant BBB defects. Mechanistically, Netrin1 enhanced Unc5B interaction with the Wnt co-receptor LRP6, induced its phosphorylation and activated Wnt/β-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin1 binding to Unc5B caused a transient disruption of Wnt signaling and BBB breakdown, followed by neurovascular barrier resealing. These data identify Netrin-Unc5B signaling as a novel regulator of BBB integrity with potential therapeutic utility for CNS diseases.

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“…[45] Dysregulation of the Notch ligand Delta-like ligand 4 (Dll4), or Notch 1 receptor expression, induces hyper-permeability and transcytosis in murine retina, while down-regulation of Notch 4 expression is associated with endothelial blood-brain barrier dysfunction. [46,47] The role of Notch activity in vascular stabilization and cell quiescence is also well-recognized. [37] In parallel, differential patterning of VE-cadherin in the absence of Notch activity supports the regulatory effects of junctional stability.…”

Section: Discussionmentioning

confidence: 99%

An embryonic zebrafish model to screen disruption of gut-vascular-barriers upon exposure to ambient ultrafine particles

Baek

Qian

Chang

et al. 2020

Preprint

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Epidemiological studies have linked exposure to ambient particulate matter (PM) with gastrointestinal (GI) diseases. Ambient ultrafine particle (UFP) are the redox-active sub-fraction of PM2.5, harboring elemental and polycyclic aromatic hydrocarbons from urban environmental sources including diesel and gasoline exhausts. The gut vascular barrier (GVB) regulates paracellular trafficking and systemic disseminations of ingested microbes and toxins. Here, we posit that acute UFP ingestion disrupts the integrity of the intestinal barrier by modulating intestinal Notch activation. Using zebrafish embryos, we performed micro-gavage with the FITC-conjugated dextran (FD10, 10 kDa) to assess the disruption of GVB integrity upon UFP exposure. Following micro-gavage, FD10 retained in the embryonic GI system, migrated through the cloaca. Conversely, co-gavaging UFP increased transmigration of FD10 across the intestinal barrier, and FD10 fluorescence occurred in the venous capillary plexus. Ingestion of UFP further impaired the mid-intestine morphology. We performed micro-angiogram of FD10 to corroborate acute UFP-mediated disruption of GVB. Transient genetic and pharmacologic manipulations of global Notch activity suggested Notch regulation of the GVB. Overall, our integration of a genetically tractable embryonic zebrafish and micro-gavage technique provided epigenetic insights underlying ambient UFP ingestion disrupts the GVB.

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Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis

Cited by 37 publications

References 89 publications

COVID-19 Morbidity and Severity in Patients With Age-Related Macular Degeneration: A Korean Nationwide Cohort Study

COVID-19 Morbidity and Severity in Patients With Age-Related Macular Degeneration: A Korean Nationwide Cohort Study

Endothelial Unc5B controls blood-brain barrier integrity

An embryonic zebrafish model to screen disruption of gut-vascular-barriers upon exposure to ambient ultrafine particles

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