Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: associations with asthmatic phenotype, airway inflammation and β2-agonist use
© Hastie et al. 2006
Received: 02 November 2005
Accepted: 15 February 2006
Published: 15 February 2006
Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo β2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion.
Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β2-adrenergic receptor haplotype determination.
Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP.
Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist. The decreased phosphorylation does not appear to be associated with a particular β2-adrenergic receptor haplotype. The observed decrease in VASP phosphorylation suggests greater inhibition of actin reorganization which is necessary for altering attachment and migration required during epithelial repair.
Attachment and migration of airway epithelial cells is an important aspect of repair of injury induced by allergens and other agents in asthma. Cytoskeletal reorganization, mediated through actin filament remodeling, is required to facilitate attachment and migration of epithelial cells into damaged areas. The vasodilator-stimulated phosphoprotein (VASP) binds to profilin, F- and G-actin, and mediates actin assembly, bundling and attachment at focal adhesions [1, 2]. VASP and two other members of the ENA/VASP family in mammalian cells, MENA (mammalian ENAbled) and EVL (ENA/VASP-like) slow or inhibit fibroblast motility by altering the dynamics of actin filament structure [3, 4]. However, MENA and EVL, despite shared molecular similarities and normal expression, did not substitute for VASP and reverse compromised cell motility in a wound healing assay of VASP-/- fibroblasts .
VASP phosphorylation occurs on two serine and one threonine (Ser 157, Ser 239 and Thr 278) through cAMP and cGMP dependent protein kinases A and G [6–9], and as recently observed in smooth muscle cells, protein kinase C . Phosphorylation by cAMP protein kinase preferentially occurs at Ser 157, whereas phosphorylation by cGMP protein kinase preferentially occurs at Ser 239, both kinases secondarily acting on Thr 278 . The Ser 157 phosphorylation results in decreased migration of the VASP molecule from 46 KD to 50 KD in SDS-gel electrophoresis [6–9]. Functionally, phosphorylation of VASP regulates its interaction with actin, and correlates with detachment and spreading of fibroblasts and epithelial cells [3, 4, 9, 11, 12]. Thus, the ratio of the 50 KD to the 46 KD molecular form of VASP within a cell sample provides a measure of VASP phosphorylation and indicates active remodeling of the actin cytoskeleton during cell attachment and migration.
We postulated that repair of injury to the airway epithelium during antigen-induced inflammation would involve enhanced phosphorylation of VASP in order to mediate actin cytoskeleton remodeling and cell migration into damaged areas. We further hypothesized that inhalation of the β-agonist albuterol, would also increase phosphorylation of VASP by stimulation of cAMP-dependent protein kinase activity, and result in altered epithelial cell attachment and mobility. These hypotheses were tested in three protocols using brush samples of airway epithelium obtained from allergic asthmatics and control subjects.
Subjects and bronchoscopic protocols
Subject demographics. Data are presented as mean ± SEM except for PC20 methacholine which are presented as the geometric means.
17 M/14 F
12 M/5 F
Age (yr): (range)
29.6 ± 1.3 (20 – 47)
27.1 ± 1.3 (21 – 33)
P = 0.22
Ragweed Skin Tests
FEV 1 (L):
3.33 ± 0.2
4.06 ± 0.2
P = 0.005
FEV 1 (% predicted):
84.8 ± 6
101.3 ± 3.7
P = 0.07
PC 20 Methacholine (mg/ml):
1.0 ± 0.8
16 at > 32 mg/ml
1 at 11 mg/ml
Serum IgE (IU/ml):
177 ± 1
51 ± 13
P = 0.002
Recovery from injury bronchoscopy protocol. Samples (lavage and brush biopsies) from four bronchoscopic procedures on each of 9 asthmatic and 7 nonasthmatic normal subjects were obtained from unchallenged and antigen (Ag) challenged lung segments according to the procedure day as indicated. A second Ag challenge on day 2 was performed to provide an additional challenged segment for day 9 without compromise from prior sampling.
(Challenged Seg 1)
(Challenged Seg 2)
β2-agonist or placebo regular inhalation and bronchoscopy protocol. Samples (lavage and brush biopsies) from five bronchoscopic procedures were obtained from the unchallenged and Ag challenged lung segments according to the procedure day indicated. Seven asthmatics enrolled in the drug arm, and 4 of these same subjects re-enrolled in the placebo arm. A baseline sample and a 24 hr post Ag challenge sample were obtained before (days 1 and 2) and after (days 18 and 19) a two week period of regular albuterol or placebo use. The initial baseline unchallenged and challenged lung segments were resampled following one additional week of regular albuterol or placebo use which were discontinued 12 hr before the final bronchoscopic procedure on day 25.
Albuterol 2 puffs, qid
Albuterol 2 puffs, qid
Cells from BAL fluid were pelleted, resuspended and counted . Aliquots of BAL cells (105 cells) from the autologous lung segment were added to medium in wells surrounding semiporous membrane culture inserts (0.4 μm pore size, Millicell-12 mm HA MCE; Millipore, Bedford, MA) containing the epithelial cell aliquots for co-culture. Cytospin preparations of BAL cells were stained, and differential counts for epithelial cells (Alcian Blue, ciliated, or other columnar cells, and their sum = "total" epithelial cell counts) were calculated (×104/ml).
Epithelial cell culture and western blot analysis of VASP
To ascertain that epithelial cells of asthmatics were responsive to β2-agonists, aliquots of epithelial cells from some asthmatics were stimulated for 2 hr after the initial 24 hr incubation with in vitro addition of albuterol (10-7 M), salmeterol (10-7 M) or no stimulus before harvest and handling as described above.
Haplotyping of β2-adrenergic receptor
DNA was isolated from cell pellets or lysates, amplified by GenomiPhi DNA kit (Amersham Biosciences, Piscataway, NJ) if low in yield, and haplotyped for the β-adrenergic receptor according to the multiplex ARMS PCR assay . DNA of 11 asthmatics and 7 nonasthmatic normals were sequenced by standard methodology  for the β-adrenergic receptor in addition to haplotyping to confirm haplotype assignment at the 13 SNP sites defined by Drysdale et al. .
Data were tested for normal distribution and equal variances by Sigmastat (version 2.0) and examined by one- or two-way repeated measures analysis of variance, post hoc pairwise comparisons by Tukey test at individual points, paired or unpaired t test, as appropriate. A p < 0.05 was considered significant, and a 0.05 < p < 0.1, a trend.
Allergen-induced inflammation effect on VASP phosphorylation
Regular inhaled β2-agonist effect on VASP phosphorylation
To confirm that the epithelial cells from asthmatics responded to both short and long-acting β2-agonists, aliquots of epithelium from four asthmatics at baseline were stimulated in vitro with either 10-7 M albuterol, 10-7 M salmeterol or unstimulated for 2 hr, and analyzed for 50/46 KD VASP. The VASP ratio in epithelial cells of all asthmatics was significantly increased by albuterol compared to unstimulated, but not by salmeterol (50 KD/46 KD VASP: 10-7 M albuterol = 0.267 ± 0.06; 10-7 M salmeterol = 0.36 ± 0.14, unstimulated = 0.11 ± 0.04; p = 0.018 for albuterol vs unstimulated, p = 0.13 for salmeterol vs unstimulated).
β2-adrenergic receptor haplotype and VASP phosphorylation
Mean of 50 KD/46 KD VASP ratio in epithelial cells according to β2-adrenergic receptor haplotype. Specific β2-adrenergic receptor haplotypes are shown with the mean ratio of 50/46 KD VASP for nonasthmatic normals or asthmatics having that haplotype. Asthmatics tended to have haplotype 4 which contains Arg at amino acid 16, and rarer haplotypes such as 1, 9, and 10 than nonasthmatic normals. The overall reduced phosphorylation of VASP (higher 50/46 KD ratio) in asthmatics compared to normals does not appear associated with a specific haplotype.
Total N = 17
N = 6
N = 5
N = 3
N = 1
N = 1
N = 1
Mean 50/46 KD
Total N = 30
N = 2
N = 9
N = 8
N = 3
N = 1
N = 2
N = 3
N = 1
N = 1
Mean 50/46 KD
Recent investigations into asthma pathogenesis have begun to focus, not on the acute inflammatory events involved with asthmatic airway inflammation, but on aberrant repair mechanisms which appear to be present [28–30]. This work focused on vasodilator-stimulated phosphoprotein (VASP) which is predicted to be involved in epithelial repair mechanisms by mediating focal adhesion, actin filament binding and polymerization, and ultimately, epithelial cell mobility. Reports published during the course of our studies have shown that detachment of kidney epithelial cells increases protein kinase A activity and its phosphorylation of VASP , as well as a transient increase in VASP expression . Although there was some increase in total VASP (46 KD + 50 KD forms) in asthmatics compared to normals on day 2 in the recovery from injury protocol, the difference was not significant, and probably does not contribute substantially to cell adherence and motility. We hypothesized that asthmatics would demonstrate increased VASP phosphorylation compared to nonasthmatic, normal subjects to permit actin remodeling and cell migration for repair of inflammatory injury. Instead, we observed a potential defect as shown by decreased VASP phosphorylation in asthmatic epithelial cells prior to and following allergen-induced injury compared to normal subjects. Increased VASP phosphorylation in response to segmental antigen challenge was modest in both asthmatic and nonasthmatic normal epithelial cells, but overall a profound decrease in the VASP phosphorylation was observed in asthmatic epithelial cells at all time points examined. The reduced VASP phosphorylation in epithelial cells of asthmatics was confirmed by expanded examination of an additional group of subjects, both asthmatic and normal (Table 4). It has been previously shown that blocking of phosphorylation at MENA Ser 236, which corresponds in molecular structure to VASP Ser 157, or depletion of ENA/VASP results in increased cell spreading and reduced functional control of cell motility in a number of model systems [3–5, 11]. More directly, 10 μM PGE1 converts 60% of the 46 KD VASP to 50 KD VASP and completely inhibits platelet aggregation as a measure of cell-cell adhesion . Thus, even partial conversion of VASP to its phosphorylated form has significant impact. This suggests one potential mechanism for aberrant epithelial repair in asthmatics: defective or diminished VASP phosphorylation may indicate abnormal epithelial motility. Confirming defective epithelial cell motility in asthmatics in vivo will be challenging, but is a necessary next step in this work.
While segmental antigen challenge did not significantly increase VASP phosphorylation in the recovery from injury protocol "a", there was a trend toward a significant increase, which was confirmed in asthmatics enrolled in the regular β-agonist inhalation protocol "b". In addition, leukocytes in bronchoalveolar lavage fluid from asthmatics co-cultured with autologous epithelium did significantly increase VASP phosphorylation, unlike the leukocytes from nonasthmatic normal subjects, suggesting a soluble signal from the BAL leukocytes to epithelial cells in asthmatics. What the signal(s) may be remains to be determined, but other work from our laboratory suggests certain growth factors such as TGFβ, could be involved.
Because VASP becomes phosphorylated by cAMP-dependent protein kinase, we also hypothesized that both in vivo and in vitro exposure of epithelial cells to a β-agonist, which increases cyclic AMP levels, should increase VASP phosphorylation. As predicted, regularly inhaled albuterol increased VASP phosphorylation in vivo and apparently altered epithelial cell adhesion, producing significantly greater numbers of epithelial cells shed into bronchoalveolar lavage fluid from unchallenged lung segments exposed only to the β-agonist, without any allergen-induced inflammation. The β-agonist effect on VASP phosphorylation was short-lived and the ratio of 50/46 KD VASP returned to baseline within 12 hr of the last albuterol inhalation in vivo. Whether the increased epithelial cell detachment induced by albuterol inhalation returns to baseline as quickly has not been determined. β-agonist use may therefore produce conflicting effects on asthmatic epithelium. β-agonists inhibit keratinocyte migration by β2-adrenergic receptor activation of the serine/threonine phosphatase PP2A , the principal phosphatase which dephosphorylates VASP , and at the same time activate cAMP-dependent protein kinase phosphorylation of VASP [6–9]. Thus, β-agonists may promote epithelial repair by enhancing both phosphorylation and dephosphorylation of VASP in actin filament restructuring, but may also promote epithelial damage by increasing the detachment of epithelial cells from the airway. These results also caution against considering as "baseline" or "control," samples obtained from asthmatics receiving β-agonist therapy without an appropriate washout interval.
Genetic variation and altered function of the β2-adrenergic receptor could potentially contribute to the differences in VASP phosphorylation observed between asthmatics and nonasthmatic normal subjects . However, examination of 50/46 KD VASP ratio grouped according to β2-adrenergic receptor haplotype for our study subjects did not reveal any specific haplotype bias, either homozygous or heterozygous, affecting VASP phosphorylation. Although the numbers of subjects in any one haplotype classification were limited, the largest 2/4 haplotype group, nonasthmatic normal subjects showed a significantly increased ratio compared to asthmatic subjects. It is possible that other characteristics of the β2-adrenergic receptor gene (for example, stability of message due to variation in the 3' untranslated region, ), variation in other components in the signaling cascade such as cAMP dependent protein kinase A [6–9], or activation of protein kinase C , genetic variation in VASP itself, or differences in the activity of protein phosphatases  between asthmatics and normals may contribute to the observed disparity in VASP phosphorylation here between asthmatic and normal subjects. Work is currently addressing these areas of inquiry.
Phosphorylation of VASP is significantly reduced in bronchial epithelial cells from asthmatics compared to nonasthmatic normal subjects, although inducible by β-agonist treatment either in vitro or in vivo. The reduced ratio of phosphorylated to unphosphorylated VASP in asthmatics does not appear associated with genetic variation in the β2-adrenergic receptor. Regular inhalation of β-agonist results in increased VASP phosphorylation in epithelial cells and increased epithelial cell detachment from the airways.
List of abbreviations
segmental allergen challenge
The authors thank their volunteer subjects who made this work possible, the Jefferson Medical College Airways Inflammation Research Group, and the Wake Forest University Cloverdale Research Facility for all their assistance with these studies. Funding for this work was obtained from NIH awards HL67663, HL69167 and AI24509, and Wake Forest University General Clinical Research Center, M01 RR 07122.
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