Potential effects of a human milk oligosaccharide 6′-sialyllactose on angiotensin II-induced aortic aneurysm via p90RSK/TGF-β/SMAD2 signaling pathway

The aberrant phenotypic transformation of vascular smooth muscle cells (VSMCs) is a key factor in the formation of aortic aneurysm (AA). This study aimed to explore the effects of 6′-sialyllactose (6′-SL), a human milk oligosaccharide, on angiotensin II (Ang II)-induced VSMC dysfunction and AA formation both in vitro and in vivo. An AA model was established in male C57BL/6 mice challenged with Ang II via osmotic pumps and a lysyl oxidase inhibitor, β-aminopropionitrile (BAPN), in drinking water. The mice were administered with 6′-SL, FMK (a p90RSK inhibitor), or losartan (as a positive control). In vitro, VSMCs were pretreated with 6′-SL before Ang II stimulation. We found that p90RSK inhibition abolished Ang II/BAPN-induced thoracic AA and abdominal AA formation. Treatment with 100 mg/kg 6′-SL significantly attenuated Ang II/BAPN-induced aortic dilatation. 6′-SL attenuated Ang II-induced collagen deposition, calcification, and immune cell accumulation. Consistently, 6′-SL downregulated p-p90RSK, p90RSK, and p-SMAD2, and mitigated VSMC contractility loss, as indicated by α-SMA expression in vivo. Interestingly, Ang II-induced transforming growth factor-beta (TGF-β) signaling pathway was suppressed by p90RSK inhibition in VSMCs. 6′-SL treatment significantly reduced TGF-β/SMAD2 targets, including dedifferentiation markers such as osteopontin and vimentin, and elastin degradation factors MMP2 and MMP9. Overexpression of p90RSK in VSMCs enhanced TGF-β and abrogated the effects of 6′-SL. Furthermore, 6′-SL co-treatment abolished high phosphate-induced calcification in vitro via p90RSK/TGF-β signaling pathway. Altogether, our findings suggest that 6′-SL could be a potential therapeutic candidate for protecting against Ang II-induced AA formation by inhibiting the p90RSK/TGF-β/SMAD2 signaling pathway.