Transcription initiation factor-1A regulates the contraction of vascular smooth muscle and maintains blood pressure.

Hypertension is a complex condition influenced by many factors. RNA polymerase I (pol I)-specific transcription initiation factor-1A (TIF-1A) regulates ribosome biosynthesis by participating in the formation of a competent pre-initiation complex. However, limited information is available regarding the role of TIF-1A in vascular smooth muscle cells (VSMCs) and its impact on blood pressure. This study investigated the biological function of TIF-1A in the modulation of smooth muscle contraction and explored the potential therapeutic targets of hypertension. Vascular smooth muscle-specific Tif-1a-knockout (Tif-1aSMKO) mice were generated by crossbreeding Tif-1aflox/flox and SMMHC-CreERT2 mice. The angiotensin II (Ang II)-infused mice and spontaneously hypertensive rats were used as animal models of hypertension. The primary mouse smooth muscle cell model induced by Ang II was used for in vitro observations. Compared to that of the control, the phenotype of the Tif-1aSMKO mice exhibited lower blood pressure. The contractile response to vasoconstrictors was also lower in mesenteric artery segments isolated from Tif-1aSMKO mice. Functional abnormalities in Tif-1aSMKO mice have been attributed to ribosomal dysfunction, which results in decreased ribosomal biosynthesis. Consistently, the expression of proteins associated with smooth muscle contraction decreased in Tif-1a-deficient smooth muscle cells. Finally, the smooth muscle-specific deletion of Tif-1a attenuated Angiotensin II-induced hypertension and vascular remodeling in mice. Administration of RNA pol I transcription inhibitor BMH-21 ameliorates hypertension in spontaneously hypertensive rats. TIF-1A regulated vascular smooth muscle contraction and maintained blood pressure by modulating ribosomal biosynthesis. Thus, TIF-1A inhibition may represent a new research orientation for the treatment of hypertension.