Abstract

Convective oxygen transport by microvessels depends on several parameters, including red blood cell flux and oxygen saturation. We demonstrate the use of intravital microscopy techniques to measure hemoglobin saturations, red blood cell fluxes and velocities, and microvessel cross-sectional areas in regions of microvascular networks containing multiple vessels. With these methods, data can be obtained at high spatial and temporal resolution and correlations between oxygen transport and hemodynamic parameters can be assessed. In vivo data are presented for a mouse mammary adenocarcinoma grown in a dorsal skinfold window chamber model.

© 2009 Optical Society of America

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2008 (4)

B. S. Sorg, M. E. Hardee, N. Agarwal, B. J. Moeller, and M. W. Dewhirst, “Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors,” J. Biomed. Opt. 13, 014026 (2008).
[CrossRef] [PubMed]

M. W. Dewhirst, Y. Cao, and B. J. Moeller, “Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response,” Nat. Rev. Cancer 8, 425-437 (2008).
[CrossRef] [PubMed]

C.-W. Lu, C.-K. Lee, M.-T. Tsai, Y.-M. Wang, and C. C. Yang, “Measurement of the hemoglobin oxygen saturation level with spectroscopic spectral-domain optical coherence tomography,” Opt. Lett. 33, 416-418 (2008).
[CrossRef] [PubMed]

A. D. Estrada, A. Ponticorvo, T. N. Ford, and A. K. Dunn, “Microvascular oxygen quantification using two-photon microscopy,” Opt. Lett. 33, 1038-1040 (2008).
[CrossRef] [PubMed]

2007 (8)

R. Michaely, A. H. Bachmann, M. L. Villiger, C. Blatter, T. Lasser, and R. A. Leitgeb, “Vectorial reconstruction of retinal blood flow in three dimensions measured with high resolution resonant Doppler Fourier domain optical coherence tomography,” J. Biomed. Opt. 12, 041213 (2007).
[CrossRef] [PubMed]

Y. Wang, B. A. Bower, J. A. Izatt, O. Tan, and D. Huang, “In vivo total retinal blood flow measurement by Fourier domain Doppler optical coherence tomography,” J. Biomed. Opt. 12, 041215 (2007).
[CrossRef] [PubMed]

L. Kagemann, G. Wollstein, M. Wojtkowski, H. Ishikawa, K. A. Townsend, M. L. Gabriele, V. J. Srinivasan, J. G. Fujimoto, and J. S. Schuman, “Spectral oximetry assessed with high-speed ultra-high resolution optical coherence tomography,” J. Biomed. Opt. 12, 041212 (2007).
[CrossRef] [PubMed]

D. Fu, T. Ye, T. E. Matthews, B. J. Chen, G. Yurtserver, and W. S. Warren, “High-resolution in vivo imaging of blood vessels without labeling,” Opt. Lett. 32, 2641-2643 (2007).
[CrossRef] [PubMed]

P. Cabrales, A. G. Tsai, and M. Intaglietta, “Is resuscitation from hemorrhagic shock limited by blood oxygen-carrying capacity or blood viscosity?” Shock Waves 27, 380-389 (2007).

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. USA 104, 19494-19499 (2007).
[CrossRef] [PubMed]

B. Styp-Rekowska, N. M. Disassa, B. Reglin, L. Ulm, H. Kuppe, T. W. Secomb, and A. R. Pries, “An imaging spectroscopy approach for measurement of oxygen saturation and hematocrit during intravital microscopy,” Microcirculation 14, 207-221 (2007).
[CrossRef] [PubMed]

D. Feng, D. Marshburn, F. Jen, R. J. Weinberg, R. M. Taylor II, and A. Burette, “Stepping into the third dimension,” J. Neurosci. 27, 12757-12760 (2007).
[CrossRef] [PubMed]

2006 (6)

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, “Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor,” Cancer Res. 66, 2219-2223 (2006).
[CrossRef] [PubMed]

F. Adhami, G. Liao, Y. M. Morozov, A. Schloemer, V. J. Schmithorst, J. N. Lorenz, R. S. Dunn, C. V. Vorhees, M. Wills-Karp, J. L. Degen, R. J. Davis, N. Mizushima, P. Rakic, B. J. Dardzinski, S. K. Holland, F. R. Sharp, and C.-Y. Kuan, “Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy,” Am. J. Pathol. 169, 566-583(2006).
[CrossRef] [PubMed]

K. G. Brurberg, M. Thuen, E.-B. M. Ruud, and E. K. Rofstad, “Fluctuations in pO2 in irradiated human melanoma xenografts,” Radiat. Res. 165, 16-25 (2006).
[CrossRef] [PubMed]

J. J. Mourad and M. Laville, “Is hypertension a tissue perfusion disorder? Implications for renal and myocardial perfusion,” J. Hypertens. 24, S10-S16 (2006).
[CrossRef]

N. V. Iftimia, D. X. Hammer, C. E. Bigelow, D. I. Rosen, T. Ustun, A. A. Ferrante, D. Vu, and R. D. Ferguson, “Toward noninvasive measurement of blood hematocrit using spectral domain low coherence interferometry and retinal tracking,” Opt. Express 14, 3377-3388 (2006).
[CrossRef] [PubMed]

C. B. Schaffer, B. Friedman, N. Nishimura, L. F. Schroeder, P. S. Tsai, F. F. Ebner, P. D. Lyden, and D. Kleinfeld, “Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion,” PLoS Biol. 4(2), e22 (2006).
[CrossRef]

2005 (8)

R. N. Pittman, “Oxygen transport and exchange in the microcirculation,” Microcirculation 12, 59-70 (2005).
[CrossRef] [PubMed]

R. L. Greenman, S. Panasyuk, X. Wang, T. E. Lyons, T. Dinh, L. Longoria, J. M. Giurini, J. Freeman, L. Khaodhiar, and A. Veves, “Early changes in the skin microcirculation and muscle metabolism of the diabetic foot,” Lancet 366, 1711-1717 (2005).
[CrossRef] [PubMed]

R. F. Gariano and T. W. Gardner, “Retinal angiogenesis in development and disease,” Nature 438, 960-966 (2005).
[CrossRef] [PubMed]

R. K. Jain, “Normalization of tumor microvasculature: an emerging concept in antiangiogenic therapy,” Science 307, 58-62 (2005).
[CrossRef] [PubMed]

K. G. Brurberg, H. K. Skogmo, B. A. Graff, D. R. Olsen, and E. K. Rofstad, “Fluctuations in pO2 in poorly and well-oxygenated spontaneous canine tumors before and during fractionated radiation therapy,” Radiother. Oncol. 77, 220-226 (2005).
[CrossRef] [PubMed]

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, “Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development,” J Biomed. Opt. 10, 044004 (2005).
[CrossRef]

L. S. Ziemer, W. M. F. Lee, S. A. Vinogradov, C. Sehgal, and D. F. Wilson, “Oxygen distribution in murine tumors: characterization using oxygen-dependent quenching of phosphorescence,” J. Appl. Physiol. 98, 1503-1510 (2005).
[CrossRef]

A. S. Golub and R. N. Pittman, “Erythrocyte-associated transients in pO2 revealed in capillaries of rat mesentery,” Am. J. Physiol. Heart Circ. Physiol. 288, H2735-H2743 (2005).
[CrossRef] [PubMed]

2004 (8)

L. I. Cardenas-Navia, D. Yu, R. D. Braun, D. M. Brizel, T. W. Secomb, and M. W. Dewhirst, “Tumor-dependent kinetics of partial pressure of oxygen flucutations during air and oxygen breathing,” Cancer Res. 64, 6010-6017 (2004).
[CrossRef] [PubMed]

P. E. James, D. Lang, T. Tufnell-Barret, A. B. Milsom, and M. P. Frenneaux, “Vasorelaxation by red blood cells and impairment in diabetes: reduced nitric oxide and oxygen delivery by glycated hemoglobin,” Circ. Res. 94, 976-983 (2004).
[CrossRef] [PubMed]

L. N. Torres, I. P. Torres Filho, R. W. Barbee, M. H. Tiba, K. R. Ward, and R. N. Pittman, “Systemic responses to prolonged hemorrhagic hypotension,”Am. J. Physiol. Heart Circ. Physiol. 286, H1811-H1820 (2004).
[CrossRef] [PubMed]

F. Gottrup, “Oxygen in wound healing and infection,” World J. Surg. 28, 312-315 (2004).
[CrossRef] [PubMed]

P. Vaupel and L. Harrison, “Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response,” Oncologist 9 (Suppl. 5), 4-9 (2004).
[CrossRef] [PubMed]

T. W. Secomb, R. Hsu, E. Y. H. Park, and M. W. Dewhirst, “Green's function methods for analysis of oxygen delivery to tissue by microvascular networks,” Ann. Biomed. Eng. 32, 1519-1529 (2004).
[CrossRef]

K. Tsukada, E. Sekizuka, C. Oshio, K. Tsujioka, and H. Minamitani, “Red blood cell velocity and oxygen tension measurement in cerebral microvessels by double-wavelength photoexcitation,” J. Appl. Physiol. 96, 1561-1568(2004).
[CrossRef]

P. Vaupel, “Tumor microenvironmental physiology and its implications for radiation oncology,” Semin. Radiat. Oncol. 14, 198-206 (2004).
[CrossRef] [PubMed]

2003 (5)

A. G. Tsai, P. C. Johnson, and M. Intaglietta, “Oxygen gradients in the microcirculation,” Physiol. Rev. 83, 933-963 (2003).
[PubMed]

P. Melis, M. L. Noorlander, A. J. van der Kleij, C. J. van Noorden, and C. M. van der Horst, “Oxygenation and microcirculation during skin stretching in undermined and nonundermined skin,” Plast. Reconstr. Surg. 112, 1295-1301(2003).
[CrossRef] [PubMed]

A. K. Dunn, A. Devor, H. Bolay, M. L. Andermann, M. A. Moskowitz, A. M. Dale, and D. A. Boas, “Simultaneous imaging of total cerebral hemoglobin concentration, oxygenation, and blood flow during functional activation,” Opt. Lett. 28, 28-30 (2003).
[CrossRef] [PubMed]

C. Hitzenberger, P. Trost, P.-W. Lo, and Q. Zhou, “Three-dimensional imaging of the human retina by high-speed optical coherence tomography,” Opt. Express 11, 2753-2761(2003).
[CrossRef] [PubMed]

H. Kerger, G. Groth, K. Kalenka, P. Vajkoczy, A. G. Tsai, and M. Intaglietta, “pO2 measurements by phosphorescence quenching: characteristics and applications of an automated system,” Microvasc. Res. 65, 32-38 (2003).
[CrossRef] [PubMed]

2002 (1)

M. A. Boegehold, “Microvascular structure and function in salt-sensitive hypertension,” Microcirculation 9, 225-241(2002).
[PubMed]

2001 (3)

J. D. Briers, “Laser Doppler, speckle and related techniques for blood perfusion mapping and imaging,” Physiol. Meas. 22, R35-R66 (2001).
[CrossRef]

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, “In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy,” Nat. Med. 7, 864-868 (2001).
[CrossRef] [PubMed]

D. Fukumura, L. Xu, Y. Chen, T. Gohongi, B. Seed, and R. K. Jain, “Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo,” Cancer Res. 61, 6020-6024 (2001).
[PubMed]

2000 (1)

A. Vadapalli, R. N. Pittman, and A. S. Popel, “Estimating oxygen transport resistance of the microvascular wall,” Am. J. Physiol. Heart Circ. Physiol. 279, 657-671 (2000).

1999 (1)

R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, “Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats,” Am. J. Physiol. 277, H551-H568 (1999).
[PubMed]

1998 (2)

J. L. Lanzen, R. D. Braun, A. L. Ong, and M. W. Dewhirst, “Variability in blood flow and pO2 in tumors in response to carbogen breathing,” Int. J. Radiat. Oncol. Biol. Phys. 42, 855-859 (1998).
[CrossRef] [PubMed]

M. W. Dewhirst, “Concepts of oxygen transport at the microcirculatory level,” Semin. Radiat. Oncol. 8, 143-150 (1998).
[CrossRef] [PubMed]

1997 (3)

J. A. Izatt, M. D. Kulkarni, S. Yazdanfar, J. K. Barton, and A. J. Welch, “In vivo bidirectional color Doppler flow imaging of picoliter blood volumes using optical coherence tomography,” Opt. Lett. 22, 1439-1441 (1997).
[CrossRef]

R. D. Shonat and P. C. Johnson, “Oxygen tension gradients and heterogeneity in venous microcirculation: a phosphorescence quenching study,” Am. J. Physiol. Heart Circ. Physiol. 272, H2233-H2240 (1997).

R. D. Shonat, E. S. Wachman, W.-H. Niu, A. P. Koretsky, and D. L. Farkas, “Near-simultaneous hemoglobin saturation and oxygen tension maps in mouse brain using an AOTF microscope,” Biophys. J. 73, 1223-1231 (1997).
[CrossRef] [PubMed]

1996 (3)

M. T. Fallon, “Rats and mice,” in Handbook of Rodent and Rabbit Medicine, K. Laber-Laird, M. M. Swindle, and P. Flecknell, eds. (Elsevier Science, 1996), pp. 1-38.

H. Kimura, R. D. Braun, E. T. Ong, R. Hsu, T. W. Secomb, D. Papahadjopoulos, K. Hong, and M. W. Dewhirst, “Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma,” Cancer Res. 56, 5522-5528 (1996).
[PubMed]

T. A. Woolsey, C. M. Rovainen, S. B. Cox, M. H. Henegar, G. E. Liang, D. Liu, Y. E. Moskalenko, J. Sui, and L. Wei, “Neuronal units linked to microvascular modules in cerebral cortex: response elements for imaging the brain,” Cereb. Cortex 6, 647-660 (1996).
[CrossRef] [PubMed]

1993 (4)

D. M. Brizel, B. Klitzman, J. M. Cook, J. Edwards, G. Rosner, and M. W. Dewhirst, “A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model,” Int. J. Radiat. Oncol. Biol. Phys. 25, 269-276 (1993).
[CrossRef] [PubMed]

E. M. Lord, L. Harwell, and C. J. Koch, “Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts,” Cancer Res. 53, 5721-5726 (1993).
[PubMed]

M. W. Dewhirst, “Angiogenesis and blood flow in solid tumors,” in Drug Resistance in Oncology, B. A. Teicher, ed. (Marcel Dekker, 1993), pp. 3-23.

J. L. Unthank, J. M. Lash, J. C. Nixon, R. A. Sidner, and H. G. Bohlen, “Evaluation of carbocyanine-labeled erythrocytes for microvascular measurements,” Microvasc. Res. 45, 193-210 (1993).
[CrossRef] [PubMed]

1991 (2)

A. C. Guyton, Textbook of Medical Physiology (W. B. Saunders, 1991).

S. Bertuglia, A. Colantuoni, G. Coppini, and M. Intaglieta, “Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation,” Am. J. Physiol. 260, H362-H372 (1991).
[PubMed]

1990 (1)

C. E. Riva, C. J. Pournaras, C. L. Poitry-Yamate, and B. L. Petrig, “Rhythmic changes in velocity, volume, and flow of blood in the optic nerve head tissue,” Microvasc. Res. 40, 36-45 (1990).
[CrossRef] [PubMed]

1989 (1)

D. P. Swain and R. N. Pittman, “Oxygen exchange in the microcirculation of hamster retractor muscle,” Am. J. Physiol. Heart Circ. Physiol. 256, H247-H255 (1989).

1988 (2)

W. G. Hundley, G. J. Renaldo, J. E. Levasseur, and H. A. Kontos, “Vasomotion in cerebral microcirculation of awake rabbits,” Am. J. Physiol. 254, H67-H71 (1988).
[PubMed]

R. K. Jain, “Determinents of tumor blood flow: a review,” Cancer Res. 48, 2641-2658 (1988).
[PubMed]

1987 (1)

M. L. Ellsworth, R. N. Pittman, and C. G. Ellis, “Measurement of hemoglobin oxygen saturation in capillaries,” Am. J. Physiol. 252, H1031-H1040 (1987).
[PubMed]

1979 (1)

B. Klitzman and B. R. Duling, “Microvascular hematocrit and red cell flow in resting and contracting striated muscle,” Am. J. Physiol. 237, H481-H490 (1979).
[PubMed]

1972 (1)

B. R. Duling, “Microvascular responses to alterations in oxygen tension,” Circ. Res. 31, 481-489 (1972).
[PubMed]

1970 (1)

B. R. Duling and R. M. Berne, “Longitudinal gradients in periarteriolar oxygen tension,” Circ. Res. 27, 669-678 (1970).
[PubMed]

Adhami, F.

F. Adhami, G. Liao, Y. M. Morozov, A. Schloemer, V. J. Schmithorst, J. N. Lorenz, R. S. Dunn, C. V. Vorhees, M. Wills-Karp, J. L. Degen, R. J. Davis, N. Mizushima, P. Rakic, B. J. Dardzinski, S. K. Holland, F. R. Sharp, and C.-Y. Kuan, “Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy,” Am. J. Pathol. 169, 566-583(2006).
[CrossRef] [PubMed]

Agarwal, N.

B. S. Sorg, M. E. Hardee, N. Agarwal, B. J. Moeller, and M. W. Dewhirst, “Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors,” J. Biomed. Opt. 13, 014026 (2008).
[CrossRef] [PubMed]

Andermann, M. L.

Bachmann, A. H.

R. Michaely, A. H. Bachmann, M. L. Villiger, C. Blatter, T. Lasser, and R. A. Leitgeb, “Vectorial reconstruction of retinal blood flow in three dimensions measured with high resolution resonant Doppler Fourier domain optical coherence tomography,” J. Biomed. Opt. 12, 041213 (2007).
[CrossRef] [PubMed]

Barbee, R. W.

L. N. Torres, I. P. Torres Filho, R. W. Barbee, M. H. Tiba, K. R. Ward, and R. N. Pittman, “Systemic responses to prolonged hemorrhagic hypotension,”Am. J. Physiol. Heart Circ. Physiol. 286, H1811-H1820 (2004).
[CrossRef] [PubMed]

Barton, J. K.

Berne, R. M.

B. R. Duling and R. M. Berne, “Longitudinal gradients in periarteriolar oxygen tension,” Circ. Res. 27, 669-678 (1970).
[PubMed]

Bertuglia, S.

S. Bertuglia, A. Colantuoni, G. Coppini, and M. Intaglieta, “Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation,” Am. J. Physiol. 260, H362-H372 (1991).
[PubMed]

Bigelow, C. E.

Blatter, C.

R. Michaely, A. H. Bachmann, M. L. Villiger, C. Blatter, T. Lasser, and R. A. Leitgeb, “Vectorial reconstruction of retinal blood flow in three dimensions measured with high resolution resonant Doppler Fourier domain optical coherence tomography,” J. Biomed. Opt. 12, 041213 (2007).
[CrossRef] [PubMed]

Boas, D. A.

Boegehold, M. A.

M. A. Boegehold, “Microvascular structure and function in salt-sensitive hypertension,” Microcirculation 9, 225-241(2002).
[PubMed]

Bohlen, H. G.

J. L. Unthank, J. M. Lash, J. C. Nixon, R. A. Sidner, and H. G. Bohlen, “Evaluation of carbocyanine-labeled erythrocytes for microvascular measurements,” Microvasc. Res. 45, 193-210 (1993).
[CrossRef] [PubMed]

Bolay, H.

Bower, B. A.

Y. Wang, B. A. Bower, J. A. Izatt, O. Tan, and D. Huang, “In vivo total retinal blood flow measurement by Fourier domain Doppler optical coherence tomography,” J. Biomed. Opt. 12, 041215 (2007).
[CrossRef] [PubMed]

Braun, R. D.

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, “Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor,” Cancer Res. 66, 2219-2223 (2006).
[CrossRef] [PubMed]

L. I. Cardenas-Navia, D. Yu, R. D. Braun, D. M. Brizel, T. W. Secomb, and M. W. Dewhirst, “Tumor-dependent kinetics of partial pressure of oxygen flucutations during air and oxygen breathing,” Cancer Res. 64, 6010-6017 (2004).
[CrossRef] [PubMed]

R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, “Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats,” Am. J. Physiol. 277, H551-H568 (1999).
[PubMed]

J. L. Lanzen, R. D. Braun, A. L. Ong, and M. W. Dewhirst, “Variability in blood flow and pO2 in tumors in response to carbogen breathing,” Int. J. Radiat. Oncol. Biol. Phys. 42, 855-859 (1998).
[CrossRef] [PubMed]

H. Kimura, R. D. Braun, E. T. Ong, R. Hsu, T. W. Secomb, D. Papahadjopoulos, K. Hong, and M. W. Dewhirst, “Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma,” Cancer Res. 56, 5522-5528 (1996).
[PubMed]

Briers, J. D.

J. D. Briers, “Laser Doppler, speckle and related techniques for blood perfusion mapping and imaging,” Physiol. Meas. 22, R35-R66 (2001).
[CrossRef]

Brizel, D.

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, “Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor,” Cancer Res. 66, 2219-2223 (2006).
[CrossRef] [PubMed]

Brizel, D. M.

L. I. Cardenas-Navia, D. Yu, R. D. Braun, D. M. Brizel, T. W. Secomb, and M. W. Dewhirst, “Tumor-dependent kinetics of partial pressure of oxygen flucutations during air and oxygen breathing,” Cancer Res. 64, 6010-6017 (2004).
[CrossRef] [PubMed]

D. M. Brizel, B. Klitzman, J. M. Cook, J. Edwards, G. Rosner, and M. W. Dewhirst, “A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model,” Int. J. Radiat. Oncol. Biol. Phys. 25, 269-276 (1993).
[CrossRef] [PubMed]

Brown, E. B.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, “In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy,” Nat. Med. 7, 864-868 (2001).
[CrossRef] [PubMed]

Brurberg, K. G.

K. G. Brurberg, M. Thuen, E.-B. M. Ruud, and E. K. Rofstad, “Fluctuations in pO2 in irradiated human melanoma xenografts,” Radiat. Res. 165, 16-25 (2006).
[CrossRef] [PubMed]

K. G. Brurberg, H. K. Skogmo, B. A. Graff, D. R. Olsen, and E. K. Rofstad, “Fluctuations in pO2 in poorly and well-oxygenated spontaneous canine tumors before and during fractionated radiation therapy,” Radiother. Oncol. 77, 220-226 (2005).
[CrossRef] [PubMed]

Burette, A.

D. Feng, D. Marshburn, F. Jen, R. J. Weinberg, R. M. Taylor II, and A. Burette, “Stepping into the third dimension,” J. Neurosci. 27, 12757-12760 (2007).
[CrossRef] [PubMed]

Cabrales, P.

P. Cabrales, A. G. Tsai, and M. Intaglietta, “Is resuscitation from hemorrhagic shock limited by blood oxygen-carrying capacity or blood viscosity?” Shock Waves 27, 380-389 (2007).

Campbell, R. B.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, “In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy,” Nat. Med. 7, 864-868 (2001).
[CrossRef] [PubMed]

Cao, Y.

M. W. Dewhirst, Y. Cao, and B. J. Moeller, “Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response,” Nat. Rev. Cancer 8, 425-437 (2008).
[CrossRef] [PubMed]

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, “Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development,” J Biomed. Opt. 10, 044004 (2005).
[CrossRef]

Cardenas-Navia, L. I.

L. I. Cardenas-Navia, D. Yu, R. D. Braun, D. M. Brizel, T. W. Secomb, and M. W. Dewhirst, “Tumor-dependent kinetics of partial pressure of oxygen flucutations during air and oxygen breathing,” Cancer Res. 64, 6010-6017 (2004).
[CrossRef] [PubMed]

Carmeliet, P.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, “In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy,” Nat. Med. 7, 864-868 (2001).
[CrossRef] [PubMed]

Chen, B. J.

Chen, Y.

D. Fukumura, L. Xu, Y. Chen, T. Gohongi, B. Seed, and R. K. Jain, “Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo,” Cancer Res. 61, 6020-6024 (2001).
[PubMed]

Colantuoni, A.

S. Bertuglia, A. Colantuoni, G. Coppini, and M. Intaglieta, “Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation,” Am. J. Physiol. 260, H362-H372 (1991).
[PubMed]

Cook, J. M.

D. M. Brizel, B. Klitzman, J. M. Cook, J. Edwards, G. Rosner, and M. W. Dewhirst, “A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model,” Int. J. Radiat. Oncol. Biol. Phys. 25, 269-276 (1993).
[CrossRef] [PubMed]

Coppini, G.

S. Bertuglia, A. Colantuoni, G. Coppini, and M. Intaglieta, “Hypoxia- or hyperoxia-induced changes in arteriolar vasomotion in skeletal muscle microcirculation,” Am. J. Physiol. 260, H362-H372 (1991).
[PubMed]

Cox, S. B.

T. A. Woolsey, C. M. Rovainen, S. B. Cox, M. H. Henegar, G. E. Liang, D. Liu, Y. E. Moskalenko, J. Sui, and L. Wei, “Neuronal units linked to microvascular modules in cerebral cortex: response elements for imaging the brain,” Cereb. Cortex 6, 647-660 (1996).
[CrossRef] [PubMed]

Dale, A. M.

Dardzinski, B. J.

F. Adhami, G. Liao, Y. M. Morozov, A. Schloemer, V. J. Schmithorst, J. N. Lorenz, R. S. Dunn, C. V. Vorhees, M. Wills-Karp, J. L. Degen, R. J. Davis, N. Mizushima, P. Rakic, B. J. Dardzinski, S. K. Holland, F. R. Sharp, and C.-Y. Kuan, “Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy,” Am. J. Pathol. 169, 566-583(2006).
[CrossRef] [PubMed]

Davis, R. J.

F. Adhami, G. Liao, Y. M. Morozov, A. Schloemer, V. J. Schmithorst, J. N. Lorenz, R. S. Dunn, C. V. Vorhees, M. Wills-Karp, J. L. Degen, R. J. Davis, N. Mizushima, P. Rakic, B. J. Dardzinski, S. K. Holland, F. R. Sharp, and C.-Y. Kuan, “Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy,” Am. J. Pathol. 169, 566-583(2006).
[CrossRef] [PubMed]

Degen, J. L.

F. Adhami, G. Liao, Y. M. Morozov, A. Schloemer, V. J. Schmithorst, J. N. Lorenz, R. S. Dunn, C. V. Vorhees, M. Wills-Karp, J. L. Degen, R. J. Davis, N. Mizushima, P. Rakic, B. J. Dardzinski, S. K. Holland, F. R. Sharp, and C.-Y. Kuan, “Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy,” Am. J. Pathol. 169, 566-583(2006).
[CrossRef] [PubMed]

Devor, A.

Dewhirst, M. W.

M. W. Dewhirst, Y. Cao, and B. J. Moeller, “Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response,” Nat. Rev. Cancer 8, 425-437 (2008).
[CrossRef] [PubMed]

B. S. Sorg, M. E. Hardee, N. Agarwal, B. J. Moeller, and M. W. Dewhirst, “Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors,” J. Biomed. Opt. 13, 014026 (2008).
[CrossRef] [PubMed]

J. Lanzen, R. D. Braun, B. Klitzman, D. Brizel, T. W. Secomb, and M. W. Dewhirst, “Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor,” Cancer Res. 66, 2219-2223 (2006).
[CrossRef] [PubMed]

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, “Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development,” J Biomed. Opt. 10, 044004 (2005).
[CrossRef]

T. W. Secomb, R. Hsu, E. Y. H. Park, and M. W. Dewhirst, “Green's function methods for analysis of oxygen delivery to tissue by microvascular networks,” Ann. Biomed. Eng. 32, 1519-1529 (2004).
[CrossRef]

L. I. Cardenas-Navia, D. Yu, R. D. Braun, D. M. Brizel, T. W. Secomb, and M. W. Dewhirst, “Tumor-dependent kinetics of partial pressure of oxygen flucutations during air and oxygen breathing,” Cancer Res. 64, 6010-6017 (2004).
[CrossRef] [PubMed]

R. D. Braun, J. L. Lanzen, and M. W. Dewhirst, “Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats,” Am. J. Physiol. 277, H551-H568 (1999).
[PubMed]

M. W. Dewhirst, “Concepts of oxygen transport at the microcirculatory level,” Semin. Radiat. Oncol. 8, 143-150 (1998).
[CrossRef] [PubMed]

J. L. Lanzen, R. D. Braun, A. L. Ong, and M. W. Dewhirst, “Variability in blood flow and pO2 in tumors in response to carbogen breathing,” Int. J. Radiat. Oncol. Biol. Phys. 42, 855-859 (1998).
[CrossRef] [PubMed]

H. Kimura, R. D. Braun, E. T. Ong, R. Hsu, T. W. Secomb, D. Papahadjopoulos, K. Hong, and M. W. Dewhirst, “Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma,” Cancer Res. 56, 5522-5528 (1996).
[PubMed]

D. M. Brizel, B. Klitzman, J. M. Cook, J. Edwards, G. Rosner, and M. W. Dewhirst, “A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model,” Int. J. Radiat. Oncol. Biol. Phys. 25, 269-276 (1993).
[CrossRef] [PubMed]

M. W. Dewhirst, “Angiogenesis and blood flow in solid tumors,” in Drug Resistance in Oncology, B. A. Teicher, ed. (Marcel Dekker, 1993), pp. 3-23.

Dinh, T.

R. L. Greenman, S. Panasyuk, X. Wang, T. E. Lyons, T. Dinh, L. Longoria, J. M. Giurini, J. Freeman, L. Khaodhiar, and A. Veves, “Early changes in the skin microcirculation and muscle metabolism of the diabetic foot,” Lancet 366, 1711-1717 (2005).
[CrossRef] [PubMed]

Disassa, N. M.

B. Styp-Rekowska, N. M. Disassa, B. Reglin, L. Ulm, H. Kuppe, T. W. Secomb, and A. R. Pries, “An imaging spectroscopy approach for measurement of oxygen saturation and hematocrit during intravital microscopy,” Microcirculation 14, 207-221 (2007).
[CrossRef] [PubMed]

Donovan, O.

B. S. Sorg, B. J. Moeller, O. Donovan, Y. Cao, and M. W. Dewhirst, “Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development,” J Biomed. Opt. 10, 044004 (2005).
[CrossRef]

Duling, B. R.

B. Klitzman and B. R. Duling, “Microvascular hematocrit and red cell flow in resting and contracting striated muscle,” Am. J. Physiol. 237, H481-H490 (1979).
[PubMed]

B. R. Duling, “Microvascular responses to alterations in oxygen tension,” Circ. Res. 31, 481-489 (1972).
[PubMed]

B. R. Duling and R. M. Berne, “Longitudinal gradients in periarteriolar oxygen tension,” Circ. Res. 27, 669-678 (1970).
[PubMed]

Dunn, A. K.

Dunn, R. S.

F. Adhami, G. Liao, Y. M. Morozov, A. Schloemer, V. J. Schmithorst, J. N. Lorenz, R. S. Dunn, C. V. Vorhees, M. Wills-Karp, J. L. Degen, R. J. Davis, N. Mizushima, P. Rakic, B. J. Dardzinski, S. K. Holland, F. R. Sharp, and C.-Y. Kuan, “Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy,” Am. J. Pathol. 169, 566-583(2006).
[CrossRef] [PubMed]

Ebner, F. F.

C. B. Schaffer, B. Friedman, N. Nishimura, L. F. Schroeder, P. S. Tsai, F. F. Ebner, P. D. Lyden, and D. Kleinfeld, “Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion,” PLoS Biol. 4(2), e22 (2006).
[CrossRef]

Edwards, J.

D. M. Brizel, B. Klitzman, J. M. Cook, J. Edwards, G. Rosner, and M. W. Dewhirst, “A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model,” Int. J. Radiat. Oncol. Biol. Phys. 25, 269-276 (1993).
[CrossRef] [PubMed]

Eickhoff, J.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. USA 104, 19494-19499 (2007).
[CrossRef] [PubMed]

Eliceiri, K. W.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. USA 104, 19494-19499 (2007).
[CrossRef] [PubMed]

Ellis, C. G.

M. L. Ellsworth, R. N. Pittman, and C. G. Ellis, “Measurement of hemoglobin oxygen saturation in capillaries,” Am. J. Physiol. 252, H1031-H1040 (1987).
[PubMed]

Ellsworth, M. L.

M. L. Ellsworth, R. N. Pittman, and C. G. Ellis, “Measurement of hemoglobin oxygen saturation in capillaries,” Am. J. Physiol. 252, H1031-H1040 (1987).
[PubMed]

Estrada, A. D.

Fallon, M. T.

M. T. Fallon, “Rats and mice,” in Handbook of Rodent and Rabbit Medicine, K. Laber-Laird, M. M. Swindle, and P. Flecknell, eds. (Elsevier Science, 1996), pp. 1-38.

Farkas, D. L.

R. D. Shonat, E. S. Wachman, W.-H. Niu, A. P. Koretsky, and D. L. Farkas, “Near-simultaneous hemoglobin saturation and oxygen tension maps in mouse brain using an AOTF microscope,” Biophys. J. 73, 1223-1231 (1997).
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Figures (12)

Fig. 1
Fig. 1

Plot of apparent hemoglobin saturation of different fractions of RBCs labeled with DiD. The absorption of the fluorescent dye is not taken into account in the hemoglobin saturation calculation in order to observe the effect of the fluorescent dye absorption. The data points are the mean ± standard deviation of a region of pixels in an image of RBCs with 100% hemoglobin saturation in a glass capillary tube. The standard deviation for the two lowest labeled fractions of RBCs is less than 1%.

Fig. 2
Fig. 2

Transmitted light image of the tumor microvessel network. White triangles represent regions of interest chosen for analysis. A 10 × objective was used for imaging (NA of 0.3, working distance of 5.5 mm ).

Fig. 3
Fig. 3

Hemoglobin saturation image of the tumor microvessel network in Fig. 2. The pixels are colored according to the hemoglobin saturation scale to the right of the figure. The background is black. Regions of interest for analysis are indicated in the figure.

Fig. 4
Fig. 4

Fluorescence image of RBCs labeled with DiD flowing in the tumor microvessel network. Images were captured with an electron multiplying CCD camera at video rates ( 30 Hz ). 20 s of data were taken every minute of the hour-long imaging session, and cells were counted over this time increment and then converted to RBC flux measurements. The locations of the regions of interest for analysis are indicated in the figure.

Fig. 5
Fig. 5

Confocal z-stack projection of the tumor microvessel network in Fig. 2. A total of 49 images were acquired at 5 μm intervals to a total depth of 245 μm by using an Olympus IV100 LSM. Regions of interest for analysis are indicated. The dashed line indicates the location of the cross-sectional area in Fig. 6.

Fig. 6
Fig. 6

Microvessel cross-sectional areas were measured from confocal image stack data. The cross-sectional area was calculated using the number of pixels in the vessel cross section and the dimensions of a pixel in the image plane. The dashed line in Fig. 5 indicates the location of the cross-sectional area.

Fig. 7
Fig. 7

Plot of RBC flux versus hemoglobin saturation (HbSat) for region of interest 1 in Fig. 2. The data points were acquired at 1 min intervals for 1 h .

Fig. 8
Fig. 8

Plot of RBC flux versus hemoglobin saturation (HbSat) for region of interest 3 in Fig. 2. The data points were acquired at 1 min intervals for 1 h .

Fig. 9
Fig. 9

Convective oxygen transport over time for regions of interest 1 and 2 in Fig. 2. Note that the values for region of interest 2 are plotted as 10 × their actual value for clarity. The oxygen transport in these vessels tends to fluctuate together, although vessel 1 is transporting about 10 × more oxygen than vessel 2. It should be noted that there was difficulty in imaging RBCs at the 6 min time point for vessel 2; so the RBC flux was interpolated for that data point.

Fig. 10
Fig. 10

Normalized power spectra for the convective oxygen transport time series data in Fig. 9 obtained by Fourier analysis. The frequency scale is given in cycles per minute (cpm).

Fig. 11
Fig. 11

Transmitted light image of the tumor microvessel network for Fig. 12. White triangles represent regions of interest chosen for analysis. Arrows indicate blood flow direction in the vessels around the regions of interest. A 10 × objective was used for imaging (NA of 0.3, working distance of 5.5 mm ).

Fig. 12
Fig. 12

Convective oxygen transport over time for regions of interest 1 and 2 in Fig. 11. The mouse initially started breathing normal air and was switched to 100% oxygen breathing during the experiment. The vertical dashed line indicates the point at which 100% oxygen breathing was started.

Tables (1)

Tables Icon

Table 1 Comparison of Tumor Microvessel Convective Oxygen Transport in Sequential Time Periods with Air Breathing Alone or Air Breathing and 100% Oxygen Breathing

Equations (4)

Equations on this page are rendered with MathJax. Learn more.

Q ox ( P O 2 ) = Q bl [ H C 0 , RBC S Hb ( P O 2 ) + α eff P O 2 ] ,
H = V RBC F RBC π R 2 v avg ,
Q ox ( P O 2 ) = π R 2 v avg [ Hb ] S Hb ( P O 2 ) C 0 , Hb ,
F RBC = N RBC t ( N RBC , fluor N RBC , total ) ,

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