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Prdm16 Amplifies Notch Signaling and Suppresses Venous Lineage Specification to Prevent Arteriovenous Malformations During Vascular Development

Van Wauwe, Jore ; Janarthanan, Pavithra ; Craps, Sander ; Kc, Ashmita ; Asuncion, Lisabel ; Vrancaert, Pieter ; Kemps, Hannelore ; Daems, Margo ; Finck, Chris and Wright, Shane , et al. (2026) In Arteriosclerosis, Thrombosis, and Vascular Biology 46(4).
Abstract

BACKGROUND: TF (transcription factor) Prdm16 (positive regulatory domain-containing protein 16) regulates hematopoietic and neuronal stem cell homeostasis, adipose differentiation, and cardiac development. Its role in the circulatory system extends beyond the heart, as Prdm16 loss in arterial endothelial cells (ECs) impairs arterial reperfusion of ischemic mouse limbs due to endothelial dysfunction, and
PRDM16 polymorphisms are associated with coronary artery disease.

METHODS: Zebrafish were used to analyze vascular development, arteriovenous endothelial specification, and the emergence of arteriovenous malformations in the absence or presence of Prdm16 or Notch signaling. Lentiviral-mediated Prdm16 overexpression in... (More)

BACKGROUND: TF (transcription factor) Prdm16 (positive regulatory domain-containing protein 16) regulates hematopoietic and neuronal stem cell homeostasis, adipose differentiation, and cardiac development. Its role in the circulatory system extends beyond the heart, as Prdm16 loss in arterial endothelial cells (ECs) impairs arterial reperfusion of ischemic mouse limbs due to endothelial dysfunction, and
PRDM16 polymorphisms are associated with coronary artery disease.

METHODS: Zebrafish were used to analyze vascular development, arteriovenous endothelial specification, and the emergence of arteriovenous malformations in the absence or presence of Prdm16 or Notch signaling. Lentiviral-mediated Prdm16 overexpression in human endothelial (progenitor) cells was coupled to qRT-PCR, Western blot, and transcriptional profiling to document Prdm16's importance for arterial lineage specification. Coimmunoprecipitation in HEK293 (human embryonic kidney 293) cells was performed to assess physical interaction between Prdm16 and the Notch pathway. Existing mouse and human data sets were reanalyzed to evaluate Prdm16 expression in mammalian arteriovenous malformations.

RESULTS: Prdm16 actively promotes arterial EC identity while suppressing venous fate. Like in mice, Prdm16 is expressed by arterial ECs early during vascular development in zebrafish, where it synergistically coordinates arterial development together with canonical notch signaling, as their combined loss in zebrafish leads to arteriovenous malformations. PRDM16's arterializing effect on human ECs is dependent on canonical Notch activity, as it is blunted in the presence of canonical Notch inhibitors and potentiated in the presence of delta-like ligand 4. Mechanistically, Prdm16 does not increase the protein levels of the cleaved intracellular domain of Notch receptors (notch intracellular domain) but rather potentiates the effect of the latter via physical and functional interaction. Prdm16 further finetunes Notch signaling and arterial development by complexing with Hey2 (Hes-related family bHLH TF with YRPW motif 2), the basic helix-loop-helix TF acting downstream of canonical Notch during arterial lineage specification and development.

CONCLUSIONS: Together, our data demonstrate an intricate interplay between Prdm16 and Notch in ECs and indicate that Prdm16 signaling may constitute a novel therapeutic target for arteriovenous malformations.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
arteriovenous malformations, endothelial cells, mice, transcription factors, zebrafish
in
Arteriosclerosis, Thrombosis, and Vascular Biology
volume
46
issue
4
article number
e323552
pages
22 pages
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:41711027
  • scopus:105034455495
ISSN
1524-4636
DOI
10.1161/ATVBAHA.125.323552
language
English
LU publication?
yes
id
222fdbe0-ef25-42d9-ba36-6aae8310efcc
date added to LUP
2026-02-26 09:27:10
date last changed
2026-06-06 11:01:17
@article{222fdbe0-ef25-42d9-ba36-6aae8310efcc,
  abstract     = {{<p>BACKGROUND: TF (transcription factor) Prdm16 (positive regulatory domain-containing protein 16) regulates hematopoietic and neuronal stem cell homeostasis, adipose differentiation, and cardiac development. Its role in the circulatory system extends beyond the heart, as Prdm16 loss in arterial endothelial cells (ECs) impairs arterial reperfusion of ischemic mouse limbs due to endothelial dysfunction, and<br>
 PRDM16 polymorphisms are associated with coronary artery disease.<br>
 </p><p>METHODS: Zebrafish were used to analyze vascular development, arteriovenous endothelial specification, and the emergence of arteriovenous malformations in the absence or presence of Prdm16 or Notch signaling. Lentiviral-mediated Prdm16 overexpression in human endothelial (progenitor) cells was coupled to qRT-PCR, Western blot, and transcriptional profiling to document Prdm16's importance for arterial lineage specification. Coimmunoprecipitation in HEK293 (human embryonic kidney 293) cells was performed to assess physical interaction between Prdm16 and the Notch pathway. Existing mouse and human data sets were reanalyzed to evaluate Prdm16 expression in mammalian arteriovenous malformations.</p><p>RESULTS: Prdm16 actively promotes arterial EC identity while suppressing venous fate. Like in mice, Prdm16 is expressed by arterial ECs early during vascular development in zebrafish, where it synergistically coordinates arterial development together with canonical notch signaling, as their combined loss in zebrafish leads to arteriovenous malformations. PRDM16's arterializing effect on human ECs is dependent on canonical Notch activity, as it is blunted in the presence of canonical Notch inhibitors and potentiated in the presence of delta-like ligand 4. Mechanistically, Prdm16 does not increase the protein levels of the cleaved intracellular domain of Notch receptors (notch intracellular domain) but rather potentiates the effect of the latter via physical and functional interaction. Prdm16 further finetunes Notch signaling and arterial development by complexing with Hey2 (Hes-related family bHLH TF with YRPW motif 2), the basic helix-loop-helix TF acting downstream of canonical Notch during arterial lineage specification and development.</p><p>CONCLUSIONS: Together, our data demonstrate an intricate interplay between Prdm16 and Notch in ECs and indicate that Prdm16 signaling may constitute a novel therapeutic target for arteriovenous malformations.</p>}},
  author       = {{Van Wauwe, Jore and Janarthanan, Pavithra and Craps, Sander and Kc, Ashmita and Asuncion, Lisabel and Vrancaert, Pieter and Kemps, Hannelore and Daems, Margo and Finck, Chris and Wright, Shane and Müller, Christian and Leigh, Nicholas D and Renné, Thomas and Ola, Roxana and Panáková, Daniela and Frye, Maike and MacRae, Calum A and Luttun, Aernout and Beerens, Manu}},
  issn         = {{1524-4636}},
  keywords     = {{arteriovenous malformations; endothelial cells; mice; transcription factors; zebrafish}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{4}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Arteriosclerosis, Thrombosis, and Vascular Biology}},
  title        = {{Prdm16 Amplifies Notch Signaling and Suppresses Venous Lineage Specification to Prevent Arteriovenous Malformations During Vascular Development}},
  url          = {{http://dx.doi.org/10.1161/ATVBAHA.125.323552}},
  doi          = {{10.1161/ATVBAHA.125.323552}},
  volume       = {{46}},
  year         = {{2026}},
}