miR-181b regulates vascular stiffness age dependently in part by regulating TGF-β signaling.
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.


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.
Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.|Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.|Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Daijiro
D
Hori
Department of Cardiovascular Pathology, Ross Research Building, Johns Hopkins University, Baltimore, Maryland, United States of America.
Brittany
B
Dunkerly-Eyring
Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.|Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Yohei
Y
Nomura
Department of Cardiovascular Pathology, Ross Research Building, Johns Hopkins University, Baltimore, Maryland, United States of America.
Debjit
D
Biswas
Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Jochen
J
Steppan
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Jorge
J
Henao-Mejia
Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Hideo
H
Adachi
Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Lakshmi
L
Santhanam
Department of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Dan E
DE
Berkowitz
Department of Cardiovascular Pathology, Ross Research Building, Johns Hopkins University, Baltimore, Maryland, United States of America.
Charles
C
Steenbergen
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Richard A
RA
Flavell
Department of Cardiovascular Pathology, Ross Research Building, Johns Hopkins University, Baltimore, Maryland, United States of America.
Samarjit
http://orcid.org/0000-0002-4377-2823
S
Das
D000375:Aging / Q000235:genetics; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002318:Cardiovascular Diseases / Q000503:physiopathology; D042783:Endothelial Cells / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics / Q000473:pathology; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009569:Nitric Oxide / Q000096:biosynthesis; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059289:Vascular Stiffness / Q000235:genetics*
D000959:Antihypertensive Agents; D035683:MicroRNAs; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; C529100:mirn181 microRNA, mouse; D000804:Angiotensin II; D009569:Nitric Oxide; D019808:Losartan