miR-181b regulates vascular stiffness age dependently in part by regulating TGF-β signaling
Daijiro Hori1,2,3, Brittany Dunkerly-Eyring4, Yohei Nomura1,2
1Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Insights
Decreased miR-181b in aging mice accelerates hypertension and arterial stiffening by increasing TGF-β signaling. Losartan treatment effectively reversed these detrimental effects, highlighting a potential therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Aging Research
Background:
- Endothelial dysfunction and arterial stiffening are key factors in cardiovascular diseases.
- The miR-181 family is implicated in vascular inflammation.
- This study investigates the role of the miR-181 family in hypertension and arterial stiffening.
Purpose of the Study:
- To determine if the miR-181 family influences hypertension and vascular stiffening.
- To elucidate the molecular mechanisms linking miR-181b, TGF-β, and vascular remodeling.
Main Methods:
- Comparison of miR-181a1/b1 knockout mice with wild-type littermates.
- Weekly measurements of pulse wave velocity (PWV) and blood pressure.
- Assessment of endothelial function, aortic modulus, and nitric oxide production.
- Analysis of TGF-β signaling pathway activation (pSMAD2/3) and intervention with losartan.
Main Results:
- miR-181a1/b1-/- mice exhibited increased PWV, systolic blood pressure, and aortic stiffness.
- Elevated serum TGF-β levels were observed in miR-181a1/b1-/- mice, with miR-181b confirmed as a direct target of TGF-β induced.
- Endothelial function and nitric oxide production were not impaired, but VSMCs showed increased TGF-β secretion.
- Losartan treatment normalized PWV, blood pressure, and vascular stiffness in knockout mice, inhibiting TGF-β signaling.
Conclusions:
- Reduced miR-181b expression during aging contributes to extracellular matrix remodeling by disinhibiting the TGF-β/pSMAD2/3 pathway.
- This pathway is a critical driver of age-related hypertension and vascular stiffening.
- Targeting the TGF-β pathway, as demonstrated by losartan, offers a potential therapeutic strategy.
Background:
Endothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family in vascular inflammation has been documented. Here we tested whether the miR-181 family can influence the pathogenesis of hypertension and vascular stiffening.
Methods And Results:
qPCR data showed a significant decrease in miR-181b expression in the aorta of the older mice. Eight miR-181a1/b1-/- mice and wild types (C57BL6J:WT) were followed weekly for pulse wave velocity (PWV) and blood pressure measurements. After 20 weeks, the mice were tested for endothelial function and aortic modulus. There was a progressive increase in PWV and higher systolic blood pressure in miR-181a1/b1-/- mice compared with WTs. At 21 weeks, aortic modulus was significantly greater in the miR-181a1/b1-/- group, and serum TGF-β was found to be elevated at this time. A luciferase reporter assay confirmed miR-181b targets TGF-βi (TGF-β induced) in the aortic VSMCs. In contrast, wire myography revealed unaltered endothelial function along with higher nitric oxide production in the miR-181a1/b1-/- group. Cultured VECs and VSMCs from the mouse aorta showed more secreted TGF-β in VSMCs of the miR-181a1/b1-/- group; whereas, no change was observed from VECs. Circulating levels of angiotensin II were similar in both groups. Treatment with losartan (0.6 g/L) prevented the increase in PWV, blood pressure, and vascular stiffness in miR-181a1/b1-/- mice. Immunohistochemistry and western blot for p-SMAD2/3 validated the inhibitory effect of losartan on TGF-β signaling in miR-181a1/b1-/- mice.
Conclusions:
Decreased miR-181b with aging plays a critical role in ECM remodeling by removing the brake on the TGF-β, pSMAD2/3 pathway.
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