Expression of latent TGF-beta binding proteins and association with TGF-beta 1 and fibrillin-1 following arterial injury.
OBJECTIVE
Transforming growth factor-beta (TGF-beta), a potent regulator of wound healing and scar formation, is thought to have a key role in the response to arterial injury. Latent TGF-beta binding proteins (LTBPs), members of the fibrillin superfamily, govern TGF-beta1 release, targeting and activation in vitro and also play a role as structural components of fibrillin-rich microfibrils. Despite the potential of LTBPs to modulate the response to arterial injury through either or both of these mechanisms, as yet their expression and function in the injured vasculature remain poorly defined.


METHODS
In this study, a porcine model of coronary angioplasty was used to investigate LTBP-1 and LTBP-2 synthesis and their association with TGF-beta 1 and fibrillin-1.


RESULTS
After angioplasty, increased LTBP-1 and LTBP-2 immunostaining was detected in a similar distribution to increased TGF-beta 1 expression in the neointima and in the neoadventitia. Overnight organ cultures revealed the formation of large latent TGF-beta 1 complexes containing LTBP-1. Increased LTBP-1 proteolysis after arterial injury correlated with increased active and latent TGF-beta levels. LTBP-2 synthesis increased in response to arterial injury but was neither present in large latent complexes nor proteolytically processed. LTBP-1 and LTBP-2 both co-localised to fibrillin-rich fibrillar structures in the neointima and adventitia.


CONCLUSIONS
These data suggest that LTBP-1 may have a TGF-beta 1 binding role in the arterial response to injury, and that LTBP-1 and LTBP-2 may have a structural role in association with microfibrils within the developing neointimal lesion. LTBP-1 proteolysis is potentially an important regulatory step for TGF-beta activation in the vasculature and inhibition of proteolysis could represent a novel therapeutic modality for controlling the arterial injury response.
Sinha
Sanjay
S
Wellcome Trust Centre for Cell-Matrix Research, 2.205 Stopford Building, University of Manchester, Manchester M13 9PT, UK.
Heagerty
Anthony M
AM
Shuttleworth
C Adrian
CA
Kielty
Cay M
CM
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D003331:Coronary Vessels / Q000293:injuries* / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D000071837:Fibrillins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009924:Organ Culture Techniques; D013552:Swine; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D017539:Tunica Intima / Q000378:metabolism; D015854:Up-Regulation
D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D000071837:Fibrillins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1