Wall Shear Stress Reduction Activates Angiotensin II to Facilitate Aneurysmal Subarachnoid Hemorrhage in Intracranial Aneurysms Through MicroRNA-29/The Growth Factor-Beta Receptor Type II/Smad3 Axis.

OBJECTIVE

We tried to broaden our knowledge of the possible role of wall shear stress (WSS) in the occurrence of intracranial aneurysms (IAs).

METHODS

Genes implicated in IAs and genes related to WSS were predicted through in silico analysis. Rat models of IAs were established, in which the expression patterns of angiotensin II (Ang II) were characterized, and WSS was assessed. Vascular endothelial cells isolated from rats bearing IAs were treated with microRNA-29 (miR-29) mimic/inhibitor, small interfering RNA-TGF-β receptor type II (TGFBR2)/overexpressed TGFBR2, Ang II, or angiotensin-converting enzyme (ACE) inhibitor. Then, the endothelial-to-mesenchymal transition (EndMT) was evaluated by flow cytometry. Finally, the volume of IAs and risk of subarachnoid hemorrhage were analyzed in vivo in response to miR-29 gain of function.

RESULTS

WSS was decreased in the IA bearing arteries, which showed a positive correlation with ACE and Ang II in the vascular tissues of IA rats. Reduced miR-29 and increased ACE, Ang II, and TGFBR2 were detected in the vascular tissues of IA rats. Ang II inhibited miR-29, which targeted TGFBR2. Downregulated TGFBR2 was accompanied by suppression of Smad3 phosphorylation. Through impairing miR-29-dependent inhibition of TGFBR2, Ang II enhanced EndMT. In vivo data confirmed that treatment of miR-29 agomir delayed the formation of IA and decreased the risk of subarachnoid hemorrhage.

CONCLUSIONS

The current study provided evidence that WSS reduction could activate Ang II, reduce miR-29 expression, and activate the TGFBR2/Smad3 axis, thus promoting EndMT and accelerating the progression of IAs.