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Spatial dependence of alveolar angiogenesis in post-pneumonectomy lung growth

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Abstract

Growth of the remaining lung after pneumonectomy has been observed in many mammalian species; nonetheless, the pattern and morphology of alveolar angiogenesis during compensatory growth is unknown. Here, we investigated alveolar angiogenesis in a murine model of post-pneumonectomy lung growth. As expected, the volume and weight of the remaining lung returned to near-baseline levels within 21 days of pneumonectomy. The percentage increase in lobar weight was greatest in the cardiac lobe (P < 0.001). Cell cycle flow cytometry demonstrated a peak of lung cell proliferation (12.02 ± 1.48%) 6 days after pneumonectomy. Spatial autocorrelation analysis of the cardiac lobe demonstrated clustering of similar vascular densities (positive autocorrelation) that consistently mapped to subpleural regions of the cardiac lobe. Immunohistochemical staining demonstrated increased cell density and enhanced expression of angiogenesis-related factors VEGFA, and GLUT1 in these subpleural regions. Corrosion casting and scanning electron microscopy 3–6 days after pneumonectomy demonstrated subpleural vessels with angiogenic sprouts. The monopodial sprouts appeared to be randomly oriented along the vessel axis with interbranch distances of 11.4 ± 4.8 μm in the regions of active angiogenesis. Also present within the regions of increased vascular density were frequent “holes” or “pillars” consistent with active intussusceptive angiogenesis. The mean pillar diameter was 4.2 ± 3.8 μm, and the pillars were observed in all regions of active angiogenesis. These findings indicate that the process of alveolar construction involves discrete regions of regenerative growth, particularly in the subpleural regions of the cardiac lobe, characterized by both sprouting and intussusceptive angiogenesis.

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Abbreviations

2D:

2-Dimensional

3D:

3-Dimensional

CL:

Cardiac lobe

IP:

Intraperitoneal

LWI:

Lung weight index

MLI:

Mean linear intercept

PBS:

Phosphate buffered saline

RLL:

Right lower lobe

RML:

Right middle lobe

RUL:

Right upper lobe

SD:

Standard deviation

SEM:

Scanning electron microscopy

TBW:

Total body weight

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Acknowledgments

This work was supported by NIH grants HL75426, HL94567 and HL007734 as well as the Uehara Memorial Foundation and the JSPS Postdoctoral Fellowships for Research Abroad.

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Authors and Affiliations

  1. Institute of Functional and Clinical Anatomy, University Medical Center of Johannes Gutenberg-University, Mainz, Germany

    Moritz A. Konerding, Jan P. Houdek & Maximilian Ackermann

  2. Laboratory of Adaptive and Regenerative Biology, Brigham and Women’s Hospital, Harvard Medical School, Room 259, Boston, MA, 02115, USA

    Barry C. Gibney, Kenji Chamoto, Grace S. Lee, Miao Lin & Steven J. Mentzer

  3. Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA

    Akira Tsuda

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  1. Moritz A. Konerding
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  2. Barry C. Gibney
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Correspondence to Steven J. Mentzer.

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Konerding, M.A., Gibney, B.C., Houdek, J.P. et al. Spatial dependence of alveolar angiogenesis in post-pneumonectomy lung growth. Angiogenesis 15, 23–32 (2012). https://doi.org/10.1007/s10456-011-9236-y

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