Vascular Smooth Muscle Contractile Function Declines With Age in Skeletal Muscle Feed Arteries.

John W Seawright,Holly C Gibbs,Samuel Padgham,Christine Chaponnier,Harini Sreenivasappa,Song Y Shin,Andreea Trache,Christopher R Woodman,Jerome P Trzeciakowski,Alvin T Yeh

doi:10.3389/fphys.2018.00856

Abstract

Aging induces a progressive decline in vasoconstrictor responses in central and peripheral arteries. This study investigated the hypothesis that vascular smooth muscle (VSM) contractile function declines with age in soleus muscle feed arteries (SFA). Contractile function of cannulated SFA isolated from young (4 months) and old (24 months) Fischer 344 rats was assessed by measuring constrictor responses of denuded (endothelium removed) SFA to norepinephrine (NE), phenylephrine (PE), and angiotensin II (Ang II). In addition, we investigated the role of RhoA signaling in modulation of VSM contractile function. Structural and functional characteristics of VSM cells were evaluated by fluorescence imaging and atomic force microscopy (AFM). Results indicated that constrictor responses to PE and Ang II were significantly impaired in old SFA, whereas constrictor responses to NE were preserved. In the presence of a Rho-kinase inhibitor (Y27632), constrictor responses to NE, Ang II, and PE were significantly reduced in young and old SFA. In addition, the age-group difference in constrictor responses to Ang II was eliminated. ROCK1 and ROCK2 content was similar in young and old VSM cells, whereas pROCK1 and pROCK2 were significantly elevated in old VSM cells. Aging was associated with a reduction in smooth muscle α-actin stress fibers and recruitment of proteins to cell-matrix adhesions. Old VSM cells presented an increase in integrin adhesion to the matrix and smooth muscle γ-actin fibers that was associated with increased cell stiffness. In conclusion, our results indicate that VSM contractile function declined with age in SFA. The decrement in contractile function was mediated in part by RhoA/ROCK signaling. Upregulation of pROCK in old VSM cells was not able to rescue contractility in old SFA. Collectively, these results indicate that changes at the VSM cell level play a central role in the reduced contractile function of aged SFA.

Highlights

Aging is associated with a progressive decline in vasoconstrictor responses in central and peripheral arteries (Delp et al, 1995; Kenney and Armstrong, 1996; Dinenno et al, 2002; Qiu et al, 2010)
These results suggest that vascular smooth muscle (VSM) contractility declines with age in skeletal muscle feed arteries (SFA) and the responses may be receptor specific
Our previous studies demonstrated that vasoconstrictor responsiveness declines with age in intact SFA (Seawright et al, 2016), an artery that plays an important role in regulating blood flow to the soleus muscle (Williams and Segal, 1993)

Summary

Introduction

Aging is associated with a progressive decline in vasoconstrictor responses in central and peripheral arteries (Delp et al, 1995; Kenney and Armstrong, 1996; Dinenno et al, 2002; Qiu et al, 2010). The mechanism responsible for the age-related decrease in vasoconstrictor function has not been fully elucidated but may involve an impaired ability of vascular smooth muscle (VSM) cells to develop contractile tension. This hypothesis is supported by evidence indicating that myogenic constrictor responses in skeletal muscle arterioles declined with age (MullerDelp et al, 2002; Kang et al, 2009; Ghosh et al, 2015). This translates to decreased responsiveness of VSM and endothelial cells to mechanical stimuli (i.e., mechanosensitivity) This impairment, in turn, induces compensatory hypertrophic or hyperplastic remodeling of aged arteries (Rizzoni et al, 2000; Najjar et al, 2005; Briones et al, 2007). An impaired ability to properly regulate vascular tone through appropriate vasoconstrictor responsiveness may lead to orthostatic intolerance, impaired blood flow distribution, and reduced exercise capacity in the elderly (Davy et al, 1998; Musch et al, 2004)

Methods

Results

Conclusion