Publications

Scholarly Journals--Published

  • Adeoye Olayemi, Silpanisong Jinjutha, Kim Dahlim, Williams James, & Pearce William. (2015). Hypoxic Remodeling of Fetal Cerebral Arteries Involves The NPY/Y1 Pathway. FASEB Journal, 29, . (04/2015)
  • Adeoye Olayemi O, Bouthors Vincent, Hubbell Margaret C, Williams James M, & Pearce William J. (2014). VEGF receptors mediate hypoxic remodeling of adult ovine carotid arteries. Journal of Applied Physiology, 117(7), 777-787. Recent studies suggest that VEGF contributes to hypoxic remodeling of arterial smooth muscle, although hypoxia produces only transient increases in VEGF that return to normoxic levels despite sustained changes in arterial structure and function. To explore how VEGF might contribute to long-term hypoxic vascular remodeling, this study explores the hypothesis that chronic hypoxia produces sustained increases in smooth muscle VEGF receptor density that mediate long-term vascular effects of hypoxia. Carotid arteries from adult sheep maintained at sea level or altitude (3,820 m) for 110 days were harvested and denuded of endothelium. VEGF levels were similar in chronically hypoxic and normoxic arteries, as determined by immunoblotting. In contrast, VEGF receptor levels were significantly increased by 107% (VEGF-R1) and 156% (VEGF-R2) in hypoxic compared with normoxic arteries. In arteries that were organ cultured 24 h with 3 nM VEGF, VEGF replicated effects of hypoxia on abundances of smooth muscle alpha actin (SM alpha A), myosin light chain kinase (MLCK), and MLC20 and the effects of hypoxia on colocalization of MLC20 with SM alpha A, as measured via confocal microscopy. VEGF did not replicate the effects of chronic hypoxia on colocalization of MLCK with SM alpha A or MLCK with MLC20, suggesting that VEGF's role in hypoxic remodeling is highly protein specific, particularly for contractile protein organization. VEGF effects in organ culture were inhibited by VEGF receptor blockers vatalinib (240 nM) and dasatinib (6.3 nM). These findings support the hypothesis that long-term upregulation of VEGF receptors help mediate sustained effects of hypoxia on the abundance and colocalization of contractile proteins in arterial smooth muscle. (10/2014) (link)
  • Adeoye Olayemi, Silpanisong Jinjutha, Williams James, Kim Dahlim, & Pearce William. (2014). Role of sympathetic innervation on cerebral artery remodeling during chronic hypoxia in fetal lambs. FASEB Journal, 28(1), . (04/2014)
  • Silpanisong Jinjutha, Kim Dahlim, Adeoye Olayemi, Thorpe Richard, & Pearce William. (2014). Chronic hypoxia differentially modulates the response of fetal ovine middle cerebral arteries to endothelin-1. FASEB Journal, 28(1), . (04/2014)
  • Adeoye O O, Butler S M, Hubbell M C, Semotiuk A, Williams J M, & Pearce W J. (2013). Contribution of increased VEGF receptors to hypoxic changes in fetal ovine carotid artery contractile proteins. American Journal of Physiology-Cell Physiology, 304(7), C656-C665. Adeoye OO, Butler SM, Hubbell MC, Semotiuk A, Williams JM, Pearce WJ. Contribution of increased VEGF receptors to hypoxic changes in fetal ovine carotid artery contractile proteins. Am J Physiol Cell Physiol 304: C656-C665, 2013. First published January 16, 2013; doi:10.1152/ajpcell.00110.2012.-Recent studies suggest that vascular endothelial growth factor (VEGF) can modulate smooth muscle phenotype and, consequently, the composition and function of arteries upstream from the microcirculation, where angiogenesis occurs. Given that hypoxia potently induces VEGF, the present study explores the hypothesis that, in fetal arteries, VEGF contributes to hypoxic vascular remodeling through changes in abundance, organization, and function of contractile proteins. Pregnant ewes were acclimatized at sea level or at altitude (3,820 m) for the final 110 days of gestation. Endothelium-denuded carotid arteries from full-term fetuses were used fresh or after 24 h of organ culture in a physiological concentration (3 ng/ml) of VEGF. After 110 days, hypoxia had no effect on VEGF abundance but markedly increased abundance of the Flk-1 (171%) and Flt-1 (786%) VEGF receptors. Hypoxia had no effect on smooth muscle alpha-actin (SM alpha A), decreased myosin light chain (MLC) kinase (MLCK), and increased 20-kDa regulatory MLC (MLC20) abundances. Hypoxia also increased MLCK-SM alpha A, MLC20-SM alpha A, and MLCK-MLC20 colocalization. Compared with hypoxia, organ culture with VEGF produced the same pattern of changes in contractile protein abundance and colocalization. Effects of VEGF on colocalization were blocked by the VEGF receptor antagonists vatalanib (240 nM) and dasatinib (6.3 nM). Thus, through increases in VEGF receptor density, hypoxia can recruit VEGF to help mediate remodeling of fetal arteries upstream from the microcirculation. The results support the hypothesis that VEGF contributes to hypoxic vascular remodeling through changes in abundance, organization, and function of contractile proteins. (04/2013) (link)
  • Hubbell M C, Semotiuk A J, Thorpe R B, Adeoye O O, Butler S M, . . . Pearce W J. (2012). Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries. American Journal of Physiology-Cell Physiology, 303(10), C1090-C1103. Hubbell MC, Semotiuk AJ, Thorpe RB, Adeoye OO, Butler SM, Williams JM, Khorram O, Pearce WJ. Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries. Am J Physiol Cell Physiol 303: C1090-C1103, 2012. First published September 19, 2012; doi:10.1152/ajpcell.00408.2011.-Chronic hypoxia increases vascular endothelial growth factor (VEGF) and thereby promotes angiogenesis. The present study explores the hypothesis that hypoxic increases in VEGF also remodel artery wall structure and contractility through phenotypic transformation of smooth muscle. Pregnant and nonpregnant ewes were maintained at sea level (normoxia) or 3,820 m (hypoxia) for the final 110 days of gestation. Common carotid arteries harvested from term fetal lambs and nonpregnant adults were denuded of endothelium and studied in vitro. Stretch-dependent contractile stresses were 32 and 77% of normoxic values in hypoxic fetal and adult arteries. Hypoxic hypocontractility was coupled with increased abundance of nonmuscle myosin heavy chain (NM-MHC) in fetal (+37%) and adult (+119%) arteries. Conversely, hypoxia decreased smooth muscle MHC (SM-MHC) abundance by 40% in fetal arteries but increased it 123% in adult arteries. Hypoxia decreased colocalization of NM-MHC with smooth muscle alpha-actin (SM-alpha A) in fetal arteries and decreased colocalization of SM-MHC with SM-alpha A in adult arteries. Organ culture with physiological concentrations (3 ng/ml) of VEGF-A(165) similarly depressed stretch-dependent stresses to 37 and 49% of control fetal and adult values. The VEGF receptor antagonist vatalanib ablated VEGF's effects in adult but not fetal arteries, suggesting age-dependent VEGF receptor signaling. VEGF replicated hypoxic decreases in colocalization of NM-MHC with SM-alpha A in fetal arteries and decreases in colocalization of SM-MHC with SM-alpha A in adult arteries. These results suggest that hypoxic increases in VEGF not only promote angiogenesis but may also help mediate hypoxic arterial remodeling through age-dependent changes in smooth muscle phenotype and contractility. (11/2012) (link)
  • Butler S M, Abrassart J M, Hubbell M C, Adeoye O, Semotiuk A, . . . Pearce W J. (2011). Contributions of VEGF to age-dependent transmural gradients in contractile protein expression in ovine carotid arteries. American Journal of Physiology-Cell Physiology, 301(3), C653-C666. Butler SM, Abrassart JM, Hubbell MC, Adeoye O, Semotiuk A, Williams JM, Mata-Greenwood E, Khorram O, Pearce WJ. Contributions of VEGF to age-dependent transmural gradients in contractile protein expression in ovine carotid arteries. Am J Physiol Cell Physiol 301: C653-C666, 2011. First published June 8, 2011; doi: 10.1152/ajpcell.00413.2010.-The present study explores the hypothesis that arterial smooth muscle cells are organized into layers with similar phenotypic characteristics that vary with the relative position between the lumen and the adventitia due to transmural gradients in vasotrophic factors. A corollary hypothesis is that vascular endothelial growth factor (VEGF) is a factor that helps establish transmural variations in smooth muscle phenotype. Organ culture of endothelium-denuded ovine carotid arteries with 3 ng/ml VEGF-A(165) for 24 h differentially and significantly influenced potassium-induced (55% increase) and stretch-induced (36% decrease) stress-strain relations in adult (n = 18) but not term fetal (n = 21) arteries, suggesting that smooth muscle reactivity to VEGF is acquired during postnatal maturation. Because inclusion of fetal bovine serum significantly inhibited all contractile effects of VEGF (adult: n = 11; fetus: n = 11), it was excluded in all cultures. When assessed in relation to the distance between the lumen and the adventitia in immunohistochemically stained coronal artery sections, expression of smooth muscle alpha-actin (SM alpha A), myosin light chain kinase (MLCK), and 20-kDa regulatory myosin light chain exhibited distinct protein-dependent and age-dependent gradients across the artery wall. VEGF depressed regional SM alpha A abundance up to 15% in adult (n = 6) but not in fetal (n = 6) arteries, increased regional MLCK abundance up to 140% in fetal (n = 8) but not in adult (n = 10) arteries, and increased regional MLC(20) abundance up to 28% in fetal arteries (n = 7) but decreased it by 17% in adult arteries (n = 9). Measurements of mRNA levels verified that VEGF receptor transcripts for both Flt-1 and kinase insert domain receptor (KDR) were expressed in both fetal and adult arteries. Overall, the present data support the unique hypothesis that smooth muscle cells are organized into lamina of similar phenotype with characteristics that depend on the relative position between the lumen and the adventitia and involve the direct effects of growth factors such as VEGF, which acts independently of the vascular endothelium in an age-dependent manner. (09/2011) (link)

Abstract

  • Adeoye O O, Silpanisong J, Williams J M, & Pearce W J. (2013). Sympathetic perivascular nerves contribute to hypoxic transformation of smooth muscle phenotype in ovine cerebral arteries. FASEB Journal, 27, 1. (04/2013)
  • Adeoye O, Silpanisong J, Bouthors V, Hlebowski V, Williams J M, & Pearce W J. (2012). Sympathetic perivascular nerves mediate remodeling effects of chronic hypoxia in fetal sheep cerebral arteries. Faseb Journal, 26, . (04/2012)