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author:("Kim, memri N")
1.  O2 Regulates Skeletal Muscle Progenitor Differentiation through Phosphatidylinositol 3-Kinase/AKT Signaling 
Molecular and Cellular Biology  2012;32(1):36-49.
Skeletal muscle stem/progenitor cells, which give rise to terminally differentiated muscle, represent potential therapies for skeletal muscle diseases. Delineating the factors regulating these precursors will facilitate their reliable application in human muscle repair. During embryonic development and adult regeneration, skeletal muscle progenitors reside in low-O2 environments before local blood vessels and differentiated muscle form. Prior studies established that low O2 levels (hypoxia) maintained muscle progenitors in an undifferentiated state in vitro, although it remained unclear if progenitor differentiation was coordinated with O2 availability in vivo. In addition, the molecular signals linking O2 to progenitor differentiation are incompletely understood. Here we show that the muscle differentiation program is repressed by hypoxia in vitro and ischemia in vivo. Surprisingly, hypoxia can significantly impair differentiation in the absence of hypoxia-inducible factors (HIFs), the primary developmental effectors of O2. In order to maintain the undifferentiated state, low O2 levels block the phosphatidylinositol 3-kinase/AKT pathway in a predominantly HIF1α-independent fashion. O2 deprivation affects AKT activity by reducing insulin-like growth factor I receptor sensitivity to growth factors. We conclude that AKT represents a key molecular link between O2 and skeletal muscle differentiation.
doi:10.1128/MCB.05857-11
PMCID: PMC3255700  PMID: 22006022
2.  Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes 
The Journal of Clinical Investigation  2012;122(4):1427-1443.
Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2α (HIF-2α) is highly expressed in vascular ECs and, along with HIF-1α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2α regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2α expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2α–deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2α–dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2α–dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2α in ECs. These results indicate that HIF-1α and HIF-2α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.
doi:10.1172/JCI57322
PMCID: PMC3314446  PMID: 22426208
3.  Direct measurement of tissue blood flow and metabolism with diffuse optics 
Diffuse optics has proven useful for quantitative assessment of tissue oxy- and deoxyhaemoglobin concentrations and, more recently, for measurement of microvascular blood flow. In this paper, we focus on the flow monitoring technique: diffuse correlation spectroscopy (DCS). Representative clinical and pre-clinical studies from our laboratory illustrate the potential of DCS. Validation of DCS blood flow indices in human brain and muscle is presented. Comparison of DCS with arterial spin-labelled MRI, xenon-CT and Doppler ultrasound shows good agreement (0.50
doi:10.1098/rsta.2011.0232
PMCID: PMC3263785  PMID: 22006897
diffuse correlation spectroscopy; blood flow; cerebral blood flow; oxygen metabolism; brain; cancer
Neurocritical care  2010;12(2):173-180.
Background
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Methods
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
Results
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
Conclusions
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
doi:10.1007/s12028-009-9305-x
PMCID: PMC2844468  PMID: 19908166
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care
Biomedical Optics Express  2010;1(4):1173-1187.
Murine hindlimb ischemia is a useful model for investigation of the mechanisms of peripheral arterial disease and for understanding the role of endothelial cells and generic factors affecting vascular regeneration or angiogenesis. To date, important research with these models has explored tissue reperfusion following ischemia with Laser Doppler methods, methods which provide information about superficial (~mm) vascular regeneration. In this work, we employ diffuse correlation spectroscopy (DCS) and diffuse optical spectroscopy (DOS) in mice after hindlimb ischemia. We hypothesize that vascular re-growth is not uniform in tissue, and therefore, since diffuse optical methods are capable of probing deep tissues, that the diffuse optics approach will provide a more complete picture of the angiogenesis process throughout the whole depth profile of the limb. Besides increased depth penetration, the combined measurements of DCS and DOS enable all-optical, noninvasive, longitudinal monitoring of tissue perfusion and oxygenation that reveals the interplay between these hemodynamic parameters during angiogenesis. Control mice were found to reestablish 90% of perfusion and oxygen consumption during this period, but oxygen saturation in the limb only partially recovered to about 30% of its initial value. The vascular recovery of mice with endothelial cell-specific deletion of HIF-2α was found to be significantly impaired relative to control mice, indicating that HIF-2α is important for endothelial cell functions in angiogenesis. Comparison of DOS/DCS measurements to parallel measurements in the murine models using Laser Doppler Flowmetry reveal differences in the reperfusion achieved by superficial versus deep tissue during neoangiogenesis; findings from histological analysis of blood vessel development were further correlated with these differences. In general, the combination of DCS and DOS enables experimenters to obtain useful information about oxygenation, metabolism, and perfusion throughout the limb. The results establish diffuse optics as a practical noninvasive method to evaluate the role of transcription factors, such as the endothelial cell-specific HIF-2α, in genetic ally modified mice.
doi:10.1364/BOE.1.001173
PMCID: PMC3018079  PMID: 21258539
(170.3880) Medical and biological imaging; (170.1420) Biology; (170.3660) Light propagation in tissues; (170.5380) Physiology
Optics express  2009;17(5):3884-3902.
“Diffuse correlation spectroscopy” (DCS) is a technology for non-invasive transcranial measurement of cerebral blood flow (CBF) that can be hybridized with “near-infrared spectroscopy” (NIRS). Taken together these methods hold potential for monitoring hemodynamics in stroke patients. We explore the utility of DCS and NIRS to measure effects of head-of-bed (HOB) positioning at 30°, 15°, 0°, −5° and 0° angles in patients with acute ischemic stroke affecting frontal cortex and in controls. HOB positioning significantly altered CBF, oxy-hemoglobin (HbO2) and total-hemoglobin (THC) concentrations. Moreover, the presence of an ipsilateral infarct was a significant effect for all parameters. Results are consistent with the notion of impaired CBF autoregulation in the infarcted hemisphere.
PMCID: PMC2724658  PMID: 19259230
Optics express  2009;17(15):12571-12581.
Four very low birth weight, very premature infants were monitored during a 12° postural elevation using diffuse correlation spectroscopy (DCS) to measure microvascular cerebral blood flow (CBF) and transcranial Doppler ultrasound (TCD) to measure macrovascular blood flow velocity in the middle cerebral artery. DCS data correlated significantly with peak systolic, end diastolic, and mean velocities measured by TCD (pA =0.036, 0.036, 0.047). Moreover, population averaged TCD and DCS data yielded no significant hemodynamic response to this postural change (p>0.05). We thus demonstrate feasibility of DCS in this population, we show correlation between absolute measures of blood flow from DCS and blood flow velocity from TCD, and we do not detect significant changes in CBF associated with a small postural change (12°) in these patients.
PMCID: PMC2723781  PMID: 19654660

Results 1-7 (7)