Key result
TLR9 deletion cuts vascular calcification ~48% in ApoE-deficient mice, driven by decreased BMP-2 expression.
Why the study?
The mechanisms underlying vascular calcification remain incompletely understood, and whether TLR9 signaling promotes vascular chondrogenesis and calcification was unknown.
Does genetic deletion of TLR9 reduce vascular calcification and chondrogenesis in ApoE-/- mice?
Does genetic deletion of TLR9 reduce vascular calcification and chondrogenesis in ApoE-/- mice?
TLR9 signaling promotes vascular calcification and chondrogenesis via macrophage-driven upregulation of BMP-2 and RANKL, suggesting TLR9 as a potential therapeutic target for vascular calcification.
Supports TLR9 targeting to mitigate vascular calcification; hypothesis-generating in mice, requiring human validation.
Vascular calcification represents a significant clinical challenge, leading to cardiovascular disease, though its underlying mechanisms remain incompletely understood. Recent studies indicate that Toll-like receptor 9 (TLR9), a key element of innate immunity, plays a pathogenic role in vascular inflammation and atherogenesis. Therefore, we hypothesized that TLR9 signaling promotes vascular chondrogenesis and calcification. We compared apolipoprotein E-deficient (ApoE-/-) mice and Tlr9-/- ApoE-/- mice after 24 -weeks high-cholesterol diet feeding. There were no differences between the groups in body weight gain, blood pressure, or plasma glucose levels, although total cholesterol levels were significantly lower in the Tlr9-/- ApoE-/- mice. The genetic deletion of TLR9 attenuated vascular calcification as determined by von Kossa staining (5.83 ± 1.14% vs. 3.04 ± 0.68%; P < 0.05), alkaline phosphatase (ALP-1) activity (P < 0.05), and chondroid matrix deposition as determined by Alcian blue staining (P < 0.05) in aortic arch compared with control mice. Immunohistostaining revealed that TLR9 deletion also decreased bone morphogenetic protein (BMP)-2 expression in aortic plaques (P < 0.05). In vitro experiments revealed that TLR9 activation by ODN1826, a TLR9 agonist, stimulated BMP-2 expression in murine peritoneal macrophages, but not in Tlr9-deficient macrophages. Although TLR9 agonists had no direct effect on vascular smooth muscle cells (VSMCs), the culture supernatants of macrophages stimulated with TLR9 agonist increased BMP-2 expression in VSMCs. TLR9 signaling promotes vascular chondrogenesis and calcification in ApoE-/- mice. Our analyses suggest that TLR9 pathway contributes to bone morphogenic activation of macrophages and VSMCs at least partially, participating in the development of vascular calcification.
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Bando et al. (2025) studied this question. TLR9 deletion reduced vascular calcification in ApoE-deficient mice, as evidenced by von Kossa staining (5.83% vs. 3.04%; P < 0.05) and decreased BMP-2 expression.
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