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Ageing causes an aortic contractile dysfunction phenotype by targeting the expression of members of the extracellular

Christopher J Nicholson1,2, Yi Xing1, Sophie Lee1

  • 1Department of Health Sciences, Boston University, Boston, MA, USA.

Journal of Cellular and Molecular Medicine
|February 19, 2022
PubMed

Insights

Aging impairs aortic contractility by downregulating extracellular signal-regulated kinase (ERK) pathway signaling. This age-related dysfunction is linked to increased microRNAs that reduce key signaling proteins, affecting vascular smooth muscle function.

Area of Science:

  • Vascular Biology
  • Molecular Signaling
  • Aging Research

Background:

  • The extracellular signal-regulated kinase (ERK) pathway regulates vascular smooth muscle cell proliferation and caldesmon, impacting vascular contractility.
  • Age-related changes in vascular function are significant, but the underlying molecular mechanisms are not fully understood.

Purpose of the Study:

  • To investigate if aortic contractile function depends on ERK activation.
  • To determine if aging affects ERK activation in aortic tissue.
  • To elucidate the molecular mechanisms behind age-related ERK downregulation.

Main Methods:

  • Biomechanical assessment of aortic contractile responses to phenylephrine in young and aged mice.
  • Inhibition of ERK signaling to assess its role in contractility.
  • Transfection of A7r5 cells and aortic tissues with miR-34a and miR-137.
  • Analysis of Src and paxillin expression and ERK phosphorylation levels.
  • Treatment with a Src inhibitor (PP2).

Main Results:

  • Contractile responses to phenylephrine were attenuated in aged mice, correlating with reduced ERK phosphorylation.
  • ERK inhibition diminished phenylephrine-induced aortic contractility, confirming ERK dependence.
  • miR-34a and miR-137 transfection in cells reduced Src, paxillin, and ERK phosphorylation.
  • In aortic tissue, miR-34a decreased Src and paxillin mRNA, and Src inhibition reduced ERK phosphorylation.
  • Aged aortas showed increased miR-34a and miR-137, decreased Src/paxillin, and impaired ERK signaling.

Conclusions:

  • Aortic contractile function is partially dependent on ERK activation.
  • Aging leads to decreased ERK phosphorylation in aortic tissue.
  • Increased miR-34a and miR-137 with aging downregulate Src and paxillin, impairing ERK signaling and causing aortic contractile dysfunction.
Keywords:
ageingfocal adhesionmicroRNAthoracic aortic aneurysmvascular smooth muscle cell

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