Sparcl1 mitigates abdominal aortic aneurysm through inhibiting lymphangiogenesis-mediated TLS formation.
Summary
Adventitial Lyve1+ vascular macrophages protect against AAA by secreting Sparcl1, which traps FGF2 to prevent dysfunctional lymphangiogenesis and tertiary lymphoid structure formation. A Sparcl1-derived peptide (Spa17) attenuated AAA progression across multiple experimental models, revealing a tractable therapeutic axis.
Key Findings
- Adventitial Lyve1+ vascular tissue-resident macrophages secrete Sparcl1, protecting against AAA progression.
- Loss of Sparcl1 in VRMs induces dysfunctional lymphangiogenesis and tertiary lymphoid structure formation, accelerating AAA.
- Sparcl1’s calcium-binding domain traps FGF2, suppressing FGF2-driven lymphangiogenesis and TLS-related gene expression.
- A Sparcl1-derived therapeutic peptide (Spa17) mitigated AAA progression across several experimental AAA models.
Clinical Implications
Targeting lymphangiogenesis/TLS formation via Sparcl1–FGF2 interactions may offer a novel disease-modifying therapy for AAA. Biomarker development around Sparcl1 or lymphatic signatures could aid risk stratification.
Why It Matters
This work uncovers a macrophage–lymphangiogenesis axis in AAA and provides a peptide-based intervention that slows disease in vivo, addressing a condition lacking effective medical therapy.
Limitations
- Preclinical models without human interventional data limit immediate clinical translatability
- Cell type–specific and context-dependent effects will require validation in human tissues and diverse AAA etiologies
Future Directions
Validate Sparcl1/lymphangiogenesis biomarkers in human AAA, optimize Spa17 pharmacology and delivery, and evaluate safety/efficacy in early-phase clinical trials.
Study Information
- Study Type
- Basic/Mechanistic study
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic experiments in animal models and cells without human interventional data
- Study Design
- OTHER