Flow-Induced Arterial Remodeling Relates to Endothelial Function in the Human Forearm

Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Circulation (Impact Factor: 14.43). 07/2008; 117(24):3126-33. DOI: 10.1161/CIRCULATIONAHA.108.778472
Source: PubMed


Chronic changes in blood flow stimulate arterial remodeling, which contributes to the maintenance of vascular homeostasis. Experimental studies suggest that remodeling represents a response to local changes in endothelial shear stress and is nitric oxide-dependent.
To investigate determinants of outward arterial remodeling in humans, we measured ulnar artery flow, diameter, and flow-mediated dilation before and after removal of the adjacent radial artery in 53 patients who were undergoing coronary bypass surgery (age 60+/-11 years; 13% female). Removal of the radial artery increased ulnar artery blood flow by 35% (P=0.009) and increased ulnar artery diameter by 9% (P<0.001) 4 to 8 weeks after surgery. At 1 week, ulnar artery shear stress was increased by 58% (P<0.001), but it was no longer different from baseline at longer-term follow-up. The contralateral ulnar artery was unaffected, which suggests that these findings were not attributable to the systemic effects of medications or the postoperative state. Extent of outward remodeling correlated with the increase in blood flow (r=0.50, P=0.001) and with flow-mediated dilation at baseline (r=0.50, P=0.001). Remodeling correlated inversely with baseline endothelial expression of P-selectin in the radial artery (r=-0.76, P=0.004, n=14).
A sustained increase in blood flow in the ulnar artery induced outward arterial remodeling despite the presence of risk factors and coronary artery disease. The remodeling response was related to endothelial phenotype, as reflected by flow-mediated dilation and expression of P-selectin. These findings provide evidence that the endothelium plays an important role in the regulation of vascular structure in humans.

Download full-text


Available from: Oz M Shapira, Oct 08, 2015
23 Reads
  • Source
    • "Experimental studies have shown that compensatory remodeling depends on the activity of nitric oxide synthase 26, and the authors of these studies recently demonstrated that the remodelling response is blunted in patients with local endothelial dysfunction. Chronic and recurrent limb ischemia stimulates compensatory formation of collateral vessels 27-30, and this response depends on the bioavailabity of nitric oxide 31-33. Thus, endothelial dysfunction may worsen the clinical status in PAD because of impaired formation of collateral vessels and remodelling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alterations of endothelial cells and the vasculature play a central role in the pathogenesis of a broad spectrum of the most dreadful of human diseases, as endothelial cells have the key function of participating in the maintenance of patent and functional capillaries. The endothelium is directly involved in peripheral vascular disease, stroke, heart disease, diabetes, insulin resistance, chronic kidney failure, tumor growth, metastasis, venous thrombosis, and severe viral infectious diseases. Dysfunction of the vascular endothelium is thus a hallmark of human diseases. In this review the main endothelial abnormalities found in various human diseases such as cancer, diabetes mellitus, atherosclerosis, and viral infections are addressed.
    International journal of biological sciences 11/2013; 9(10):1057-1069. DOI:10.7150/ijbs.7502 · 4.51 Impact Factor
  • Source
    • "Such therapies to promote vascular growth and function are needed to prevent the progression of peripheral arterial disease (Gornik 2009). Significant evidence has accumulated that oxidative stress and a proinflammatory state are associated with impaired flow-mediated remodeling and collateral growth in animals and humans (Vita et al. 2008; Ziegler et al. 2010) and that antioxidant therapy reverses this impairment. Our results support the hypothesis that abnormal transcription factor activation and gene expression mediate, at least in part, the impairment of collateral growth in the SHR. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Analysis of global gene expression in mesenteric control and collateral arteries was used to investigate potential molecules, pathways, and mechanisms responsible for impaired collateral growth in the Spontaneously Hypertensive Rat (SHR). A fundamental difference was observed in overall gene expression pattern in SHR versus Wistar Kyoto (WKY) collaterals; only 6% of genes altered in collaterals were similar between rat strains. Ingenuity® Pathway Analysis (IPA) identified major differences between WKY and SHR in networks and biological functions related to cell growth and proliferation and gene expression. In SHR control arteries, several mechano-sensitive and redox-dependent transcription regulators were downregulated including JUN (-5.2×, P = 0.02), EGR1 (-4.1×, P = 0.01), and NFĸB1 (-1.95×, P = 0.04). Predicted binding sites for NFĸB and AP-1 were present in genes altered in WKY but not SHR collaterals. Immunostaining showed increased NFĸB nuclear translocation in collateral arteries of WKY and apocynin-treated SHR, but not in untreated SHR. siRNA for the p65 subunit suppressed collateral growth in WKY, confirming a functional role of NFkB. Canonical pathways identified by IPA in WKY but not SHR included nitric oxide and renin-angiotensin system signaling. The angiotensin type 1 receptor (AGTR1) exhibited upregulation in WKY collaterals, but downregulation in SHR; pharmacological blockade of AGTR1 with losartan prevented collateral luminal expansion in WKY. Together, these results suggest that collateral growth impairment results from an abnormality in a fundamental regulatory mechanism that occurs at a level between signal transduction and gene transcription and implicate redox-dependent modulation of mechano-sensitive transcription factors such as NFĸB as a potential mechanism.
    07/2013; 1(2):e0005. DOI:10.1002/phy2.5
  • Source
    • "The above data are consistent with the evolving hypothesis that arterial shear stress is a homeostatically regulated variable (Vita et al. 2008). In this conceptual framework, shear stress mediated arterial enlargement, which is at least partly NO-dependent, acts to mitigate the increases in transmural pressure and wall stress brought about by repeated exercise bouts (Guyton and Hartley 1985; Langille et al. 1989; Lloyd et al. 2001; Prior et al. 2003; Tronc et al. 1996; Rodbard and Sarzana 1975; Zamir 1977). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct "vascular deconditioning and conditioning" effects which likely modify cardiovascular risk.
    Arbeitsphysiologie 11/2009; 108(5):845-75. DOI:10.1007/s00421-009-1260-x · 2.19 Impact Factor
Show more