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The Proceedings of the American Thoracic Society 6:673-677 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200907-064DP
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Measurement and Impact of Remodeling in the Lung

Airway Neovascularization in Asthma

Robert J. Bischof1,2, Jane E. Bourke3, Stuart J. Hirst1, Els N. T. Meeusen2, Kenneth J. Snibson4 and Joanne Van Der Velden4

The Melbourne Lung Biology Network: 1 Airway Pathobiology Laboratory, Department of Physiology, and 2 Biotechnology Research Laboratories, Department of Physiology, Monash University, Melbourne, Victoria, Australia; 3 Department of Pharmacology, and 4 Centre for Animal Biotechnology, University of Melbourne, Parkville, Victoria, Australia

Correspondence and requests for reprints should be addressed to Stuart J. Hirst, Ph.D., Department of Physiology, Monash University, Clayton Campus, Melbourne, Victoria 3800, Australia. E-mail: stuart.hirst{at}med.monash.edu.au

ABSTRACT

Expansion of the airway wall vascular compartment has recently been established as a feature of asthma involving both enlargement of existing vascular structures and the formation of new vessels (angiogenesis). Both processes are likely to occur together and are fundamental for supporting the many aspects of tissue inflammation and remodeling manifest in the clinical symptoms of airway disease. Multiple growth factors are implicated in airway angiogenesis, with vascular endothelial growth factor among the most important. Other asthma-associated stimuli, including ADAM33, environmental tobacco smoke, and rhinovirus infection, are emerging as proangiogenic regulators. Increasing attention is also focused on the complex interplay of airway wall inflammatory and structural cells, including airway smooth muscle in driving expansion of the bronchial submucosal vascular plexus in asthma. Here, we provide a brief update on recent developments in this emerging area and highlight the potential role played by airway smooth muscle.

Key Words: angiogenesis • bronchial circulation • airway vasculature • inflammation • airway smooth muscle

Airway remodeling occurring in conjunction with, or because of, chronic airway inflammation, refers to changes in normal tissue architecture that persist in the airways of miscellaneous diseases, including asthma (1, 2). Airway remodeling begins early in the course of the disease and results in alterations in the content and/or composition of airway epithelial, submucosal extracellular matrix, smooth muscle, and vascular compartments that lead to thickening of the airway wall (3) and the development of incompletely reversible airway narrowing, airway hyperresponsiveness, and reduced airway distensibility (4, 5). Importantly, airway remodeling in both large and small airways has been documented across the range of asthma severities (5), and includes significant qualitative and quantitative increases in the bronchial submucosal microvascular plexus that supplies blood to the tissues of the inner airway wall (4, 6). This short review focuses on some of the possible mediators and cells that drive changes in this vascular compartment in airway wall remodeling in asthma. Excellent recent accounts focused on the targeting of vascular remodeling in asthma by current therapy can be found elsewhere (7–11).

AIRWAY VASCULARITY AND ITS SIGNIFICANCE IN ASTHMA

Early studies on the pathology of asthma reported that an edematous bronchial mucosa, with dilated and congested blood vessels, was associated with fatal disease (2, 12). These observations have been confirmed in more recent morphometric studies of postmortem lung tissue and endobronchial biopsies from subjects with asthma. These report increases of approximately two- to threefold in the total number of vessels and in the vascular area of medium and small airways, compared with healthy control subjects (13–15) (Figures 1A and 1B), that reflect asthma severity (15–17). Indirect correlates supporting increased airway vascularity in individuals with asthma include elevated baseline airway mucosal blood flow as well as increased breath temperature and exhaled nitric oxide (9, 14). Finally, the use of high-magnification endobronchovideoscopy has recently allowed direct visualization of the bronchial vessels of the submucosal plexus, confirming the presence of an increased airway mucosal and functional vascular network (Figures 1C and 1D) even in early phases of chronic adult asthma (18). Increases in the tracheobronchial microcirculation in asthma are presumed to involve multiple mechanisms, including neovascularization, vascular dilatation, and hyperpermeability (10). The precise temporal sequence for these changes is unknown, although a recent study has demonstrated increased airway wall vascularity that was present in children with mild to moderate asthma, suggesting airway neovascularization may occur early in the progression of asthma (19).


Figure 1
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  		Figure 1. (A, C) Increased airway wall vascularity in patients with asthma compared with (C, D) healthy control subjects assessed in histological sections of endobronchial biopsies (upper panels) or by high-magnification endobronchovideoscopy (lower panels). Arrows indicate blood vessels in the lamina propria. Reproduced by permission from References 13 and 18.

 
Future studies in experimental animal models may allow the time course of development of vascular remodeling in asthma to be defined. Large animals are highly suited to such studies because they have well-developed bronchial microcirculations. Chronic exposure of sheep airways to house dust mite (HDM) allergen results in deterioration in lung function (20) with concomitant features of airway remodeling, such as epithelial and airway smooth muscle cell changes (21). A component of this HDM-induced remodeling in sheep includes expansion of the vascular compartment in the lamina propria (Figure 2). Similarly, chronic exposure to aerosolized HDM allergen in primates results in increased airway wall vascularity that is airway-generation dependent, being greater in mid to lower airways, and is associated with a concomitant reduction in lung function (22).


Figure 2
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  		Figure 2. Collagen IV immunoreactivity in hematoxylin-counterstained histological sections showing increased airway vascularity in sheep exposed to repeated segmental allergen challenges of house dust mite. (A) A representative section of an airway exposed to allergen compared with (B) a non-exposed control airway. Arrows indicate blood vessels in the lamina propria and in the outer airway wall.

 
Consequences of airway vascularity increases in asthma have not been fully elucidated, but theoretically could be either beneficial or detrimental. Increased mucosal vascularity and blood flow could enhance delivery of systemically administered medication to the airway and accelerate the clearance of locally produced spasmogens. However, on balance, mucosal hypervascularity is more likely to contribute to the clinical manifestations of asthma (23). The hyperpermeability accompanying hypervascularity could enhance airway tissue swelling to promote the effects of airway smooth muscle accumulation and contraction by reactively contributing to airway wall thickening, airway lumen narrowing, and loss of airway distensibility (24). As well as promoting increased clearance of inhaled antiasthma medications, the increase in airway vascularity may also serve to amplify inflammatory cell adhesion and trafficking and support the enhanced metabolic demands of wider tissue remodeling processes, including cellular proliferation.

ANGIOGENESIS

Expansion of the airway wall vascular compartment in asthma may arise from enlargement of existing vascular structures, without the formation of new vessels, as well as by angiogenesis, which is the formation of new blood vessels from existing ones. Both processes may occur simultaneously and result from endothelial cell proliferation and migration, recruitment of perivascular supporting cells (pericytes), and a maturation process (6, 7). Angiogenesis is a tightly regulated process mediated by a balance between proangiogenic and antiangiogenic factors. The former include endothelial cell-restricted tyrosine kinase receptor ligands, including vascular endothelial growth factor (VEGF), and the angiopoietins working together with growth factors such as fibroblast growth factor (FGF)-2, angiogenin, and cytokines and chemokines such as IL-6 and IL-8. Diseased or injured tissues produce and release these factors into the nearby tissues to bind to cognate surface receptors on endothelial cells of nearby preexisting blood vessels. The most necessary and sufficient angiogenic protein is VEGF, which has at least four splice-variants, of which VEGF121 is the most studied in the lung (25). The importance of VEGF in inflammatory and vascular remodeling processes and the recent appreciation of its role in many of the classic pathogenic features of asthmatic airways has led some investigators to describe it as "the molecule of the decade" (7).

Angiogenesis is countered by multiple antiangiogenic factors that include arresten, canstatin, tumstatin, restin, and endostatin (7, 8), although little is known of their respective roles in neovascularization in asthma. Thus, the switch to the angiogenic phenotype in the bronchial vascular compartment likely involves a change in the local equilibrium between these positive and negative regulators of the extant growth of microvessels (8).

DRIVERS OF THE ANGIOGENIC PROCESS IN ASTHMA

Angiogenesis can be visualized by the appearance of small cystic out-pouchings or angiogenic "sprouts" from parent blood vessels. In an unconfirmed report, these have been shown to be increased in number in the airway wall submucosa of patients with asthma (26). These authors also report a skew in distribution to smaller vessel size, consistent with the formation of recent vascular structures. Although the mechanisms triggering the angiogenic switch in asthma are unknown, initial studies show an imbalance between proangiogenic and protective antiangiogenic factors in asthmatic airways (27). Exaggerated levels of the endothelial mitogen and permeability factor, VEGF, its receptors VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1) (26–29), and other proangiogenic factors such as FGF-2 (28, 30), angiogenin (28, 29, 31), and monocyte chemoattractant protein-1 (29) have been detected in tissue and airway lining fluid from individuals with asthma, including children (31, 32). These observations correlate directly with increased total airway vascular area (26–28, 33–35) and disease severity (31, 36) and are inversely correlated with airway caliber and airflow obstruction (27, 28, 31, 33).

Feltis and colleagues (26) provided a careful examination of the expression of VEGFR1 (a high-affinity inhibitory decoy receptor believed to modulate VEGF activity), VEGFR2 (the active proangiogenic receptor), and angiopoietin (Ang)-1 (a vessel maturation factor) in endobronchial biopsies from individuals with asthma. Labeling for both VEGFR1 and VEGFR2 tended to be increased in asthma. However, subjects with asthma had relatively more VEGFR1-positive than VEGFR2-positive vessels. The increase in absolute amount of VEGFR2, along with an increase in the VEGFR1:VEGFR2 ratio, in subjects with asthma might suggest that VEGFR1 is serving as a braking mechanism to enhance VEGF-VEGFR2 activity. These intriguing findings suggest that in addition to reports of increased vascularity and VEGF expression in asthma, there may also be an apparent resetting of the VEGFR system (26) that deserves further investigation. In the same study, increases in Ang-1–positive vessels were also detected in asthma, but this was only in proportion with the increase in the number of vessels, with no change in Ang-1 immunoreactivity per vessel (26). Consistent with little change in Ang-1 levels in tissue, Simcock and colleagues found that Ang-1 was barely detectable in bronchoalveolar lavage fluid from people with mild asthma or healthy control subjects (29), and a recent study has suggested that Ang-1, when present, may protect against increased airway inflammation and airways hyperresponsiveness in a murine asthma model (37).

To date, endostatin is the only endogenous antiangiogenic factor that has been studied in asthma. Suzaki and colleagues reported that administration of endostatin to ovalbumin-sensitized mice inhibited airway hyperresponsiveness, pulmonary allergic inflammation, and production of ovalbumin-specific IgE and markers of lung inflammation (38). These investigators also examined the expression of PECAM-1/CD31 (a vascular endothelial cell marker) and found it was reduced in the endostatin-treated mice. Asai and colleagues showed levels of both VEGF and endostatin to be increased in asthmatic compared with nonasthmatic sputum samples (27). An imbalance was shown in the VEGF/endostatin ratio in subjects with asthma compared with subjects without asthma that reflected increased levels of VEGF over those of endostatin (27). Simcock and colleagues reported similar findings in the VEGF/endostatin and angiogenin/endostatin ratios in bronchoalveolar lavage fluid from subjects with asthma and showed that bronchoalveolar lavage fluid from subjects with asthma but not from healthy subjects induced VEGF-dependent vascular tubule formation in vitro (29). Collectively, these studies suggest VEGF is a key angiogenic factor in vivo and that airway angiogenesis is an ongoing feature of stable asthma.

Other asthma-associated stimuli are emerging as proangiogenic regulators. ADAM33 (a disintegrin and metalloprotease) is an asthma susceptibility gene whose polymorphic variation has been linked to asthma and airway hyperresponsiveness, but not to indices of allergic inflammation. ADAM33 polymorphism also predicts impaired lung function in young children, suggesting that ADAM33 may contribute to the early life origins of asthma (39). Since its discovery in 2002, ADAM33 has been extensively characterized at the molecular and structural level but its biological role and its direct contribution to asthma pathogenesis have remained elusive. Recently, Puxeddu and colleagues reported that the catalytic domain of ADAM33, but not its inactive mutant, caused rapid induction of endothelial cell differentiation in vitro, and neovascularization ex vivo and in vivo. It was also demonstrated that the profibrotic mediator transforming growth factor (TGF)-β2 enhanced release or shedding of a soluble form of ADAM33 to promote angiogenesis. This demonstration of a role for ADAM33 in directly promoting angiogenesis is the first time that ADAM33 has been shown to function as a remodeling gene product that can act independently of airway inflammation (40). Notably, in the airway wall ADAM33 colocalizes to airway smooth muscle and fibroblast-like cells in the submucosa (41, 42), supporting its link with airway hyperresponsiveness (39) and airway (vascular) remodeling (40).

Finally, exposure to environmental tobacco smoke is known to contribute to and exacerbate asthma. The prevalence of smoking in the population with asthma is estimated to be between 25% and 30% in some countries (43). In a recent study by Rao and colleagues exposure of mice for 12 weeks to environmental tobacco smoke induced angiogenesis of lung microvessels associated with selectin-mediated increases in intravascular leukocyte rolling and adhesion compared with fresh air–exposed lungs (44). This is consistent with other studies suggesting that smoking may be sufficient to support leukocyte recruitment and local tissue inflammation to contribute to remodeling of the airways of smokers without asthma and/or promote continued remodeling in individuals with asthma (45).

CELLULAR SOURCES OF ANGIOGENIC FACTORS IN ASTHMA

It has been recognized that angiogenic factors derive not only from endothelial cells but also from key inflammatory cells involved in asthma (28, 34). Colocalization studies have revealed that CD34-positive cells, eosinophils (46), macrophages (28), and mast cells (34, 47) colocalized with VEGF and/or angiogenin and correlated with the degree of submucosal vascularity. Zanini and colleagues showed that in the airways of subjects with mild to moderate asthma there was a marked increase in both total mast cells and chymase-positive mast cells, which may be a major source of VEGF production (48), with 28% of the latter cells being labeled for VEGF. The VEGF-stained cells, as well as the chymase-positive cells, were correlated with increased vascular density and airway hyperresponsiveness and were positively related to the ratio of chymase-positive to total mast cells (48).

Attention has also been focused on the role of tissue eosinophils in airway neovascularization in asthma (46) after the observation that supernatants from human peripheral blood eosinophils induce angiogenic sprouting in cultured rat aorta rings and in the chick embryo chorioallantoic model (49). Recently, it was demonstrated that in addition to VEGF production from eosinophils, the specific eosinophil mediator major basic protein possesses proangiogenic activity (50).

Last, VEGF and angiogenesis may provide a link between innate immune activation and adaptive Th2-type immune responses with structural changes in the airways. Psarras and colleagues found that VEGF in human nasal washings was increased during rhinovirus-associated asthma exacerbations and that cultured human bronchial epithelial cells infected with rhinovirus showed increased VEGF production (51), the latter confirmed by De Silva and colleagues (52). Supernatants from these epithelial cell cultures were also shown to induce the formation in vitro of primitive endothelial tubules, which was prevented by VEGF neutralization (51).

AIRWAY SMOOTH MUSCLE AND AIRWAY WALL ANGIOGENESIS

Appreciation of the role of airway smooth muscle in respiratory disease progression has advanced significantly with the recognition that airway smooth muscle expresses an array of mediators that influence vascular reactivity and angiogenesis, recently reviewed in (8). Furthermore, the bronchial circulation, comprising the submucosal microvascular plexus, is anatomically juxtaposed between the epithelium and the increased airway smooth muscle mass found in asthmatic airways (5, 13). As a result, the distance between the airway smooth muscle and the epithelium can be reduced (53), increasing the proximity of vessels to the airway smooth muscle (Figures 1A and 1B).

Immunohistochemical studies of human airways show positive VEGF immunoreactivity in airway smooth muscle (54, 55). Cultured airway smooth muscle cells also express VEGF protein, both constitutively and incrementally, after stimulation by the proasthmatic inflammatory mediators, including IL-1β, tumor necrosis factor-{alpha}, TGFβ, and IL-13 (8). Furthermore, airway smooth muscle cells from individuals with asthma exhibit enhanced constitutive release of multiple proangiogenic factors, including VEGF, angiogenin, and Ang-1, with TGFβ1 further increasing the production of VEGF from these airway smooth muscle cells (56).

Recently, interactions between airway smooth muscle cells and endothelial cells have been studied in relation to angiogenesis as a means of proliferating airway smooth muscle providing for its increased dependency on mitochondrial metabolic energy pathways for proliferation in asthma (57). Several in vitro models have paved the way to decipher these cellular interactions, including induction of primitive vascular tubules by airway smooth muscle–derived VEGF (56, 58). Cell conditioned medium from a mechanical strain airway smooth muscle model has been shown to be angiogenic with increased levels of hypoxia-inducible factor 1{alpha}, a transcription factor for VEGF expression, leading to induction of vascular tubule formation in vitro (58). In another study, conditioned medium from airway smooth muscle from subjects with asthma, but not healthy control subjects, induced marked vascular tube formation (Figure 3) that was abrogated by VEGF depletion (56). In addition, TGFβ1 was shown to further increase the production of VEGF from airway smooth muscle cells from subjects with asthma and to up-regulate the capacity of these cells to induce the formation of vascular tubules (56). Exogenous application of proangiogenic mediators (VEGF, Ang-1, and angiogenin), produced in elevated amounts by airway smooth muscle from subjects with asthma, to endobronchial biopsies from healthy volunteers increased tissue vascularity ex vivo to levels similar to those reported in bronchial biopsies from patients with asthma (56). Together, these observations strongly suggest that airway smooth muscle has an important role in promoting vascular remodeling and angiogenesis in asthma.


Figure 3
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  		Figure 3. Airway smooth muscle cells from subjects with asthma constitutively promote in vitro angiogenesis. Light photomicrographs show increased numbers of primitive vascular tubules (labeled with CD31, an endothelial cell marker) after culture with (A) conditioned media from airway smooth muscle cells isolated from a subject with moderate asthma, or (B) from a healthy donor. In the graph (C), the capacity of airway smooth muscle from subjects with mild (Mild A) or moderate asthma (Mod A) to induce angiogenesis (increased number of vascular tubules per field of view [FOV]) is shown relative to 1 ng/ml VEGF (right-hatched bars) or spontaneous tubule formation (left-hatched bars). *P < 0.05, **P < 0.01, ***P < 0.001. Reproduced with permission from Reference 56.

 
In contrast, the role played by airway smooth muscle in regulating inhibitory effects on angiogenesis remains to be clarified, although an initial study indicates levels of antiangiogenic factors (e.g., endostatin) are not different between cells cultured from subjects with or without asthma, despite increased release of proangiogenic mediators including VEGF from asthmatic airway smooth muscle (56). Clearly, airway smooth muscle has important synthetic functions that can contribute to the imbalance in angiogenic factors present in the remodeled airway. In asthma, the scale appears to be tipped in favor of proangiogenic mediators with airway smooth muscle being intimately involved in this outcome.

CONCLUSIONS

Airway microvascular changes are now well established as remodeling features typical of asthma. Mucosal hypervascularity in asthma can contribute to airway narrowing and airflow reduction by angiogenic processes as well as vasodilatation and increased microvascular permeability. Current in vivo and in vitro findings indicate that substantial cross-talk exists between the constituent cellular components of the bronchial microvasculature and infiltrating and/or resident inflammatory and structural cells through the coordinated release of multiple angiogenic growth factors and cytokines.

VEGF has a fundamental role among the angiogenic factors identified, although other asthma-related stimuli, including ADAM33, environmental tobacco smoke, and rhinovirus infection, may also have important roles in driving or sustaining airway wall hypervascularity. In addition, airway smooth muscle is emerging as a key player in the induction of remodeling of the airway circulation. It is also possible that airway smooth muscle regulates angiogenesis (Figure 3) to match the metabolic requirements arising from its increased content in the airway wall in asthma (56). At present, our knowledge of the onset and progression of vascular remodeling and angiogenesis in asthma is far from complete. With further understanding of the mechanisms involved in the functional and angiogenic changes in airway blood vessels in asthma, the potentially important therapeutic implications of targeting the bronchial circulation in disease will become apparent.

FOOTNOTES

Supported by Asthma UK, grant 07/034, and National Health and Medical Research Council (NHMRC) of Australia, grant 566904.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form July 13, 2009; accepted in final form August 20, 2009)

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