Andrographolide ameliorates vascular injury in hypertension by suppressing EndMT via Sp1-Notch1 signaling

Endothelial-to-mesenchymal transition (EndMT) is a potential therapeutic target for hypertension-induced vascular injury. Andrographolide (AGP) is a bioactive labdane diterpenoid that confers cardiovascular protective effects. However, the role of AGP in regulating EndMT during hypertension-related vascular injury is not clear.

In this study, we investigated the effect of AGP on EndMT in vascular injury and elucidated its underlying mechanism in hypertension.

Angiotensin II (Ang II)-induced hypertensive mice were used to evaluate the vascular protective effects of AGP. Mechanistic experiments were performed in Ang II-stimulated endothelial cells. We detected EndMT markers both in vitro and in vivo. We also conducted a small-scale clinical trial to assess the effects of AGP on vascular damage in patients with hypertension.

In Ang II-induced hypertensive mice, AGP improved endothelial function, alleviated arterial stiffness, and decreased aortic remodeling while also lowering blood pressure. It also suppressed EndMT in hypertensive mice and Ang II-treated endothelial cells. Quantitative co-immunofluorescence staining of aortic sections revealed that the percentage of CD31/vimentin double-positive cells was significantly higher in Ang II-induced hypertensive mice, whereas AGP treatment considerably decreased this proportion. Endothelial Notch1 expression was upregulated during EndMT, whereas genetic or pharmacological inhibition of Notch1 blocked Ang II-induced EndMT. Ang II downregulated the expression of Sp1, whereas the overexpression of Sp1 mitigated Ang II-induced EndMT; moreover, knocking down Sp1 abrogated the protective effects of AGP. In mice, the overexpression of Sp1 via adeno-associated virus 9 or Notch1 inhibition attenuated vascular injury by suppressing EndMT. Moreover, AGP improved flow-mediated dilation and reduced brachial-ankle pulse wave velocity in hypertensive patients (ChiCTR2300071970).

We found that AGP ameliorates hypertension-induced vascular injury by inhibiting EndMT through the Sp1-Notch1 pathway. These findings suggest that AGP may serve as a promising therapeutic candidate for restoring vascular homeostasis in patients suffering from hypertension.