Background:
MicroRNA-133a (miR133a) is a small non-coding RNA, which represses the translation of multiple mRNAs. This laboratory has reported an inverse relationship between aortic diameter and miR133a abundance in aortic tissue from patients with thoracic aortic aneurysm (TAA); as diameter increased, the abundance of miR133a decreased. Given that wall tension at a given pressure increases with increasing vessel diameter (Law of LaPlace), this study tested the hypothesis that elevated aortic wall tension results in a loss of miR-133a.
Methods/Results:
TAA was induced in wild type mice using an established murine model (0.5M CaCl
2
application, 15 min). MiR133a abundance (QPCR) was reduced in TAA tissue (3-wk TAA, 42.1±8.6% p<0.05 vs mice without TAA (100%)). In two
in vivo
models of elevated wall tension (
simulated hypertension
): 1) ANGII (angiotensin II infusion; 1.44mg/kg/day), and 2) BPH2 (spontaneously hypertensive mice, The Jackson Laboratory, Stock #003005), miR133a levels were decreased compared to normotensive controls (ANGII: 53.0±4.3%; BPH2: 51.7±7.0%; p<0.05 vs normotensive control (100%)). Aortic rings from wild type mice were hung on parallel wires in an
ex vivo
tissue myograph at 0.7 g, then ANGII (100nM) was added to the tissue baths, which generated increased tension (1.21±0.15g) and resulted in reduced tissue miR133a abundance (46.0±12%; p<0.05 vs no AngII,). Furthermore, increased tension alone (1.5g, 3 hr) resulted in decreased tissue miR133a abundance (39.0±7.0%; p<0.05 vs 0.7 g tension). Isolated primary aortic cell lines (fibroblasts (FB) and smooth muscle cells (SMC)) were exposed to biaxial cyclic stretch for 3 hr. FB miR133a was reduced (62.8±8.3%; p<0.05 vs unstretched control (100%)), while SMC miR133a abundance remained unchanged.
Conclusion:
The significance of these unique findings is 2-fold: First, tension alone was sufficient to decrease miR133a abundance in aortic tissue. Second, increased tension reduced miR133a abundance in FB, a cell type that is responsible for extracellular matrix remodeling. These findings suggest changes in wall tension alone (
hypertension
) may be associated with pathological extracellular matrix remodeling, in part, through the loss of miR133a in fibroblasts.
In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts