Molecular Changes Implicate Angiogenesis and Arterial Remodeling in Systemic Sclerosis–Associated and Idiopathic Pulmonary Hypertension Article Swipe
Yuechen Zhou
,
Tracy Tabib
,
Mengqi Huang
,
Ke Yuan
,
Yunhye Kim
,
Christina Morse
,
John Sembrat
,
Eleanor Valenzi
,
Robert Lafyatis
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1161/atvbaha.123.320005
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1161/atvbaha.123.320005
BACKGROUND: Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH. METHODS: We analyzed single-cell RNA sequencing profiles of endothelial and perivascular mesenchymal populations from explanted lung tissue of patients with SSc-associated PH (n=16), idiopathic pulmonary arterial hypertension (n=3), and healthy controls (n=15). Findings were validated by immunofluorescence staining of explanted human lung tissue. RESULTS: Three disease-associated endothelial populations emerged. Two angiogenic endothelial cell (EC) subtypes markedly expanded in SSc-associated PH lungs: tip ECs expressing canonical tip markers PGF and APLN and phalanx ECs expressing genes associated with vascular development, endothelial barrier integrity, and Notch signaling. Gene regulatory network analysis suggested enrichment of Smad1 (SMAD family member 1) and PPAR-γ (peroxisome proliferator-activated receptor-γ) regulon activities in these 2 populations, respectively. Mapping of potential ligand-receptor interactions highlighted Notch, apelin-APJ (apelin receptor), and angiopoietin-Tie (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) signaling pathways between angiogenic ECs and perivascular cells. Transitional cells, expressing both endothelial and pericyte/smooth muscle cell markers, provided evidence for the presence of endothelial-to-mesenchymal transition. Transcriptional programs associated with arterial endothelial dysfunction implicated VEGF-A (vascular endothelial growth factor-A), TGF-β1 (transforming growth factor beta-1), angiotensin, and TNFSF12 (tumor necrosis factor ligand superfamily member 12)/TWEAK (TNF-related weak inducer of apoptosis) in the injury/remodeling phenotype of PH arterial ECs. CONCLUSIONS: These data provide high-resolution insights into the complexity and plasticity of the pulmonary endothelium in SSc-associated PH and idiopathic pulmonary arterial hypertension and provide direct molecular insights into soluble mediators and transcription factors driving PH vasculopathy.
Related Topics
Concepts
Angiogenesis
Pulmonary hypertension
Endothelial dysfunction
Vascular remodelling in the embryo
Angiopoietin
Biology
Pathology
Angiopoietin receptor
Endothelial stem cell
Pericyte
Medicine
Vascular endothelial growth factor
Internal medicine
Cancer research
Endocrinology
In vitro
VEGF receptors
Biochemistry
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1161/atvbaha.123.320005
- OA Status
- green
- Cited By
- 13
- References
- 89
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4399386645
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4399386645Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1161/atvbaha.123.320005Digital Object Identifier
- Title
-
Molecular Changes Implicate Angiogenesis and Arterial Remodeling in Systemic Sclerosis–Associated and Idiopathic Pulmonary HypertensionWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-06-06Full publication date if available
- Authors
-
Yuechen Zhou, Tracy Tabib, Mengqi Huang, Ke Yuan, Yunhye Kim, Christina Morse, John Sembrat, Eleanor Valenzi, Robert LafyatisList of authors in order
- Landing page
-
https://doi.org/10.1161/atvbaha.123.320005Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.ncbi.nlm.nih.gov/pmc/articles/11269037Direct OA link when available
- Concepts
-
Angiogenesis, Pulmonary hypertension, Endothelial dysfunction, Vascular remodelling in the embryo, Angiopoietin, Biology, Pathology, Angiopoietin receptor, Endothelial stem cell, Pericyte, Medicine, Vascular endothelial growth factor, Internal medicine, Cancer research, Endocrinology, In vitro, VEGF receptors, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
13Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 11, 2024: 2Per-year citation counts (last 5 years)
- References (count)
-
89Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.2 | 161 |
| abstract_inverted_index.a | 5, 13 |
| abstract_inverted_index.1) | 151, 183 |
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| abstract_inverted_index.Two | 104 |
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| abstract_inverted_index.Notch, | 170 |
| abstract_inverted_index.VEGF-A | 218 |
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| abstract_inverted_index.cells. | 191 |
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