Key result
Inhibiting endothelial cell junctional instability and vascular leakage with the synthetic metabolite UAS03 effectively mitigated ANGPTL2-driven vasculopathy and inhibited fibrogenesis in a mouse model of systemic sclerosis.
Why the study?
Vasculopathy is a common hallmark of fibrotic disorders including systemic sclerosis, but its underlying etiology and contribution to fibrogenesis remain ill defined.
Does UAS03 mitigate vasculopathy and inhibit fibrogenesis in a mouse model of systemic sclerosis?
Does UAS03 mitigate vasculopathy and inhibit fibrogenesis in a mouse model of systemic sclerosis?
Inhibiting ANGPTL2-driven endothelial cell junctional instability with UAS03 mitigates vasculopathy and fibrogenesis in a mouse model of systemic sclerosis.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for UAS03 in systemic sclerosis; human validation required before clinical consideration.
Vasculopathy is a common hallmark of various fibrotic disorders, including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill defined. In SSc, the vasculopathy typically precedes the onset of fibrosis, and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction, and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that angiopoietin-like protein 2 (ANGPTL2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, ANGPTL2 upregulates profibrotic genes, downregulates various junctional proteins, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and, consequently, vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, ANGPTL2 is a promising early biomarker of the disease, and inhibiting the vasculopathy-inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to treatment of fibrotic diseases by targeting vascular defects.
No takes yet. Share an insight, caveat, or question.
Saha et al. (2025) studied Systemic sclerosis. UAS03 vs. Vehicle control was evaluated on Vascular leakage and dermal thickness. Inhibiting endothelial cell junctional instability and vascular leakage with the synthetic metabolite UAS03 effectively mitigated ANGPTL2-driven vasculopathy and inhibited fibrogenesis in a mouse model of systemic sclerosis.
Synapse has enriched 10 related papers. Consider them for comparative context: