Key Takeaways & Executive Findings
- •• • CCA at 270.3 mg/kg for 8 weeks increased collagen volume fraction and epidermal/dermal thickness with P<0.01–0.001, directly counteracting D-galactose-induced dermal atrophy and restoring mechanical skin integrity. • • Serum Ang1/Ang2 ratio rose to near-normal levels (P<0.001) while PDGFRβ expression increased, indicating enhanced pericyte coverage and vascular maturation—critical for reducing leaky, pro-inflammatory microvessels in aged skin. • • In H2O2-stressed HUVEC, CCA (62.5–250.0 μg/mL) reduced SA-β-gal positivity and ROS (P<0.001) and downregulated p53, p21, and VEGFA (P<0.05–0.001), demonstrating direct endothelial protection and suppression of senescence-associated secretory phenotype. • • CCA upregulated p-Tie2 and VE-cadherin (P<0.001) and improved pericyte recruitment and barrier integrity, providing a mechanistic basis for stabilizing endothelial junctions and reducing vascular permeability in aging microenvironments.
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Abstract
D-galactose-induced premature aging in mice and H2O2-stressed human umbilical vein endothelial cells (HUVEC) were used to evaluate Colla Corii Asini (CCA) at 270.3 mg/kg (8-week oral gavage) and 62.5–250.0 μg/mL (24-h pretreatment), respectively. CCA restored skin architecture, increased epidermal/dermal thickness and collagen volume fraction (P<0.01, 0.001), improved perfusion, reduced disorganized angiogenesis, elevated PDGFRβ and serum Ang1/Ang2 ratio (P<0.001), and suppressed IL-1β, CXCL1, and TNF-α (P<0.001). In HUVEC, CCA reduced SA-β-gal positivity and ROS (P<0.001), downregulated SASP/inflammatory genes (P<0.01, 0.001), upregulated p-Tie2 and VE-cadherin (P<0.001), downregulated p53, p21, Tie2, and VEGFA (P<0.05, 0.001), increased Ang1/Ang2 (P<0.05, 0.01), and enhanced pericyte recruitment and endothelial barrier integrity. The data indicate that CCA mitigates skin aging and microvascular instability through modulation of the Tie2/Ang/VE-cadherin axis, providing a multi-target natural intervention for age-related microcirculatory dysfunction.
1. Introduction
Current anti-aging interventions rely predominantly on exogenous antioxidants or single-target small molecules, which show limited efficacy in restoring microvascular architecture and carry unresolved long-term safety concerns. Skin aging is intimately linked to microvascular degeneration, yet clinically approved agents that simultaneously address endothelial senescence, pericyte loss, and barrier dysfunction remain unavailable. The absence of therapies that target vascular maturation and stability leaves a critical gap in managing age-related skin atrophy and microcirculatory disorders.
This study addresses that bottleneck by evaluating Colla Corii Asini (CCA), a traditional Chinese medicine with documented antioxidant and tissue-protective properties, in a D-galactose-induced murine model and an H2O2-induced HUVEC stress model. The protocol specifically interrogates the Tie2/Ang/VE-cadherin axis—a key regulator of endothelial barrier function and pericyte recruitment—to determine whether CCA can restore Ang1/Ang2 balance, enhance VE-cadherin expression, and improve vascular maturity. By combining laser speckle contrast imaging, optical coherence tomography angiography, and molecular analyses, the work provides a mechanistic framework for CCA as a multi-target intervention against skin aging and microvascular instability.
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ZHAO Yujia, SUN Yanan, GAO Xinyu, LIU Haibin, WANG Yi (2026). Mechanism of Colla Corii Asini on Improving D-Galactose-Induced Skin Aging and Microvascular Homeostasis via the Tie2/Ang/VE-cadherin Signaling Axis. Chinese Traditional and Herbal Drugs. https://doi.org/10.7501/j.issn.0253-2670.2026.16.20261613
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Frequently Asked Questions
What is the quantitative evidence that CCA restores vascular maturation rather than merely increasing vessel density?
CCA increased serum Ang1/Ang2 ratio to near-normal levels (P<0.001) and elevated PDGFRβ expression (P<0.001), indicating enhanced pericyte coverage. In HUVEC, CCA upregulated p-Tie2 and VE-cadherin (P<0.001) while downregulating VEGFA (P<0.05–0.001), shifting the angiogenic profile from sprouting to stabilization. These molecular changes were accompanied by reduced disorganized angiogenesis in OCTA and improved pericyte recruitment in functional assays, confirming maturation rather than simple density increase.
How does CCA perform under oxidative stress conditions that typically induce endothelial senescence?
In H2O2-induced HUVEC, CCA (62.5–250.0 μg/mL) reduced SA-β-gal positivity and ROS levels (P<0.001), downregulated SASP and inflammatory genes (P<0.01–0.001), and suppressed p53 and p21 protein expression (P<0.05–0.001). These results demonstrate direct protection against oxidative stress-driven premature senescence, with a concomitant increase in Ang1/Ang2 ratio (P<0.05–0.01) and enhanced endothelial barrier integrity.
What are the translational limitations of using a D-galactose-induced model to claim anti-aging efficacy?
The D-galactose model recapitulates accelerated aging phenotypes but does not fully replicate natural chronological aging. The study acknowledges that the H2O2-induced HUVEC model represents stress-induced premature senescence rather than replicative senescence. Therefore, while the data show significant improvements in SA-β-gal, ROS, p16, p21, p53, and SASP markers, further validation using cell cycle arrest metrics and aged animal models is required to confirm clinical relevance.
Can CCA be scaled for clinical use given its complex composition and lack of target specificity?
The study used a defined dose of 270.3 mg/kg in mice and 62.5–250.0 μg/mL in vitro, demonstrating reproducible pharmacological effects. However, the active constituents and target specificity remain unresolved. The authors explicitly state that the material basis, target specificity, and clinical translation value require further verification. Industrial scalability will depend on standardized extraction and quality control to ensure batch-to-batch consistency of the active fractions.
What is the mechanistic link between Tie2/Ang modulation and the observed anti-inflammatory effects?
CCA increased Ang1/Ang2 ratio (P<0.001 in vivo, P<0.05–0.01 in vitro), promoting Tie2 phosphorylation (P<0.001) and VE-cadherin upregulation (P<0.001). This axis stabilizes endothelial junctions and reduces vascular leakiness, which in turn lowers inflammatory cytokine expression (IL-1β, CXCL1, TNF-α; P<0.001). The data align with known Ang1-mediated suppression of vascular permeability and inflammation, providing a direct mechanistic bridge between Tie2 activation and the observed anti-inflammatory outcomes.
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