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Physiological and Pathological Angiogenesis in the Adult Pulmonary Circulation

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Angiogenesis occurs during growth and physiological adaptation in many systemic organs, for example, exercise‐induced skeletal and cardiac muscle hypertrophy, ovulation, and tissue repair. Disordered angiogenesis contributes to chronic inflammatory disease processes and to tumor growth and metastasis. Although it was previously thought that the adult pulmonary circulation was incapable of supporting new vessel growth, over that past 10 years new data have shown that angiogenesis within this circulation occurs both during physiological adaptive processes and as part of the pathogenic mechanisms of lung diseases. Here we review the expression of vascular growth factors in the adult lung, their essential role in pulmonary vascular homeostasis and the changes in their expression that occur in response to physiological challenges and in disease. We consider the evidence for adaptive neovascularization in the pulmonary circulation in response to alveolar hypoxia and during lung growth following pneumonectomy in the adult lung. In addition, we review the role of disordered angiogenesis in specific lung diseases including idiopathic pulmonary fibrosis, acute adult distress syndrome and both primary and metastatic tumors of the lung. Finally, we examine recent experimental data showing that therapeutic enhancement of pulmonary angiogenesis has the potential to treat lung diseases characterized by vessel loss. © 2011 American Physiological Society. Compr Physiol 1:1473‐1508, 2011.

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Figure 1. Figure 1.

Microscopic images of semithin (1 μ) resin‐embedded sections stained with toluidine blue from alveolar walls of normoxic and hypoxic rat lung following 2 weeks of exposure to hypoxia (Fio2 = 0.10). (Panel A) Image taken from control lung showing numerous capillaries within the alveolar wall. (Panel B) Image of an alveolar wall taken from chronically hypoxic lung tissue. Some capillaries appear to protrude from the alveolar wall into the alveolar lumen, a pattern not seen in control lungs. (Scale bar indicates 10 μm, ×100 objective). Reproduced with permission from Howell et al. 170.

Figure 2. Figure 2.

Schematic representation of oxygen uptake in a pulmonary alveolus at normal (Panel A) and reduced (Panels B and C) partial pressures of inspired oxygen (PIo2). The plots show partial pressure of oxygen in capillary blood (Pco2) rising progressively toward that of alveolar gas (PAo2) as blood traverses the alveolar capillary. Under resting conditions, RBC transit time in the alveolar capillary is 0.75 s. This reduces during exercise as blood flow velocity increases due to increased cardiac output; a representative value of 0.25 s is used here for illustrative purposes. The partial pressure of oxygen in the blood at the time of entry into the capillary is that of mixed venous blood (Pvo2). Resting values of Pvo2 fall with reducing PIo2; further reductions are seen during exercise but, for simplicity, these are not illustrated here. At normal PIo2, there is a large partial pressure gradient between alveolar gas and mixed venous blood resulting in a rapid rate of diffusion of oxygen across the alveolar capillary membrane so that equilibration is achieved before the capillary blood leaves the alveolus, both at rest and during exercise. With moderate reductions in PIo2, the reduced gradient between the alveolar gas and the mixed venous blood reduces the rate of oxygen transfer but this is still sufficient to allow equilibration at rest. However, with reduced transit time during exercise equilibration is not achieved so oxygen uptake becomes diffusion limited. At the lowest values of PIo2, diffusion limitation is seen both at rest and during exercise. Note all values shown are representative, not exact. The principles illustrated in this schematic are based on data and concepts elucidated by Wagner, West, Weibel, Scheid and colleagues 202,294,295,393,394,402,408,409.

Figure 3. Figure 3.

Postmortem angiogram demonstrating extensive neovascularization in a lung from a patient with IPF (right panel) as compared to normal lung (left panel). Photomicrograph kindly provided by Professor Dame Margaret Turner‐Warwick M.D, Ph.D., FRCP and reproduced by permission from Keane et al. (Inflammation injury and Repair. In: Textbook of Respiratory Medicine, edited by Mason R, Broaddus C, Murray J. and Nadel J. Philadelphia: Elsevier, 2005, p. 449‐490).

Figure 1.

Microscopic images of semithin (1 μ) resin‐embedded sections stained with toluidine blue from alveolar walls of normoxic and hypoxic rat lung following 2 weeks of exposure to hypoxia (Fio2 = 0.10). (Panel A) Image taken from control lung showing numerous capillaries within the alveolar wall. (Panel B) Image of an alveolar wall taken from chronically hypoxic lung tissue. Some capillaries appear to protrude from the alveolar wall into the alveolar lumen, a pattern not seen in control lungs. (Scale bar indicates 10 μm, ×100 objective). Reproduced with permission from Howell et al. 170.

Figure 2.

Schematic representation of oxygen uptake in a pulmonary alveolus at normal (Panel A) and reduced (Panels B and C) partial pressures of inspired oxygen (PIo2). The plots show partial pressure of oxygen in capillary blood (Pco2) rising progressively toward that of alveolar gas (PAo2) as blood traverses the alveolar capillary. Under resting conditions, RBC transit time in the alveolar capillary is 0.75 s. This reduces during exercise as blood flow velocity increases due to increased cardiac output; a representative value of 0.25 s is used here for illustrative purposes. The partial pressure of oxygen in the blood at the time of entry into the capillary is that of mixed venous blood (Pvo2). Resting values of Pvo2 fall with reducing PIo2; further reductions are seen during exercise but, for simplicity, these are not illustrated here. At normal PIo2, there is a large partial pressure gradient between alveolar gas and mixed venous blood resulting in a rapid rate of diffusion of oxygen across the alveolar capillary membrane so that equilibration is achieved before the capillary blood leaves the alveolus, both at rest and during exercise. With moderate reductions in PIo2, the reduced gradient between the alveolar gas and the mixed venous blood reduces the rate of oxygen transfer but this is still sufficient to allow equilibration at rest. However, with reduced transit time during exercise equilibration is not achieved so oxygen uptake becomes diffusion limited. At the lowest values of PIo2, diffusion limitation is seen both at rest and during exercise. Note all values shown are representative, not exact. The principles illustrated in this schematic are based on data and concepts elucidated by Wagner, West, Weibel, Scheid and colleagues 202,294,295,393,394,402,408,409.

Figure 3.

Postmortem angiogram demonstrating extensive neovascularization in a lung from a patient with IPF (right panel) as compared to normal lung (left panel). Photomicrograph kindly provided by Professor Dame Margaret Turner‐Warwick M.D, Ph.D., FRCP and reproduced by permission from Keane et al. (Inflammation injury and Repair. In: Textbook of Respiratory Medicine, edited by Mason R, Broaddus C, Murray J. and Nadel J. Philadelphia: Elsevier, 2005, p. 449‐490).

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Paul McLoughlin, Michael P. Keane. Physiological and Pathological Angiogenesis in the Adult Pulmonary Circulation. Compr Physiol 2011, 1: 1473-1508. doi: 10.1002/cphy.c100034