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

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.

Vascular smooth muscle cell contractile function and mechanotransduction

“…However, ECM deformation was used to assess the vasoconstrictor response and given that aged arteries are stiffer than their younger counterparts, VSMC actomyosin activity may remain intact [97] . In agreement with this, cell-matrix adhesions were subjected to increased mechanical load in aged arteries, compared to their younger counterparts [96] . Further investigation is now required to assess whether the mechanisms of VSMC actomyosin signaling is influenced by matrix stiffness.…”

“…For example, a recent study investigated the ex-vivo vasoconstrictor response of young and old soleus muscle feed arteries. Despite an upregulation of ROCK activity, there was a decreased constrictor response in the aged vessels [96] . Aged VSMCs were incapable of generating sufficient force to induce matrix remodeling [96] .…”

“…Despite an upregulation of ROCK activity, there was a decreased constrictor response in the aged vessels [96] . Aged VSMCs were incapable of generating sufficient force to induce matrix remodeling [96] . However, ECM deformation was used to assess the vasoconstrictor response and given that aged arteries are stiffer than their younger counterparts, VSMC actomyosin activity may remain intact [97] .…”

“…As described above, matrix stiffness influences both the expression of VSMC contractile proteins and the ability of VSMCs to physically contract and deform their surrounding ECM. Therefore, stiffened ECM is no longer remodeled by the intrinsic actomyosin activity of the VSMCs [96] . However, this does not explain whether the absence of substrate deformation is due to a decline in VSMC actomyosin response or because the ECM has become too stiff to be manipulated.…”

Transcriptome analysis of mouse aortae reveals multiple novel pathways regulated by aging

“…This is consistent with the notion that aging is a physiological and chronic process attributable to low grade perturbation of multifactorial pathways. A recent study from feed arteries of soleus muscle in rats reported that aged vessels exhibited a decrement in SMC contractility, mainly owing to the impairment of RhoA/ROCK signaling and significant decreased SMα-actin fibers [ 47 ]. This is somewhat inconsistent with our current findings wherein genes encoding both cyto-contractile and contraction regulatory proteins (see GSE145972) were insignificantly attenuated.…”