Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Perturbed VEGF Signalling within the Pulmonary Vasculature of a TGF Dependent Mouse Model of Systemic Sclerosis.

Derrett-Smith2,  Emma C., Dooley2,  Audrey, Baliga1,  Reshma, Hobbs1,  Adrian, MacAllister1,  Raymond, Abraham4,  David, Denton3,  Christopher P.

Centre for Clinical Pharmacology, Rayne Institute, UCL, London, Canada
Centre for Rheumatology and Connective Tissue Diseases, Royal Free Campus, UCL Medical School, London
Royal Free Hospital, London, United Kingdom
University College London, London, United Kingdom


Vascular complications of systemic sclerosis (SSc) are a major cause of mortality and morbidity. A role for altered VEGF signaling in PAH-SSc is supported by data that correlate circulating VEGF with mPAP at diagnosis. There is also a trend for VEGF levels to fall after initiation of PAH-specific therapy. High circulating VEGF levels may be a marker of repair in response to vascular injury. We have therefore examined VEGF signaling in a TGFb-dependent mouse model of SSc with evidence of a constitutive pulmonary vasculopathy.


The transgenic mouse strain TbRIIDk-fib expresses a kinase-deficient type II TGFb receptor driven by a fibroblast-specific promoter leading to balanced ligand-dependent upregulation of TGFb signalling. Pulmonary vasculopathy was confirmed by histological assessment of vessel architecture, isolated organ bath and in vivo haemodynamic studies performed on adult male transgenic and littermate wildtype animals (n=8 in each group). Biochemical analysis of the VEGF and endothelin axes were performed assessing RNA by quantitative PCR and protein by Western blotting using cultured aortic and pulmonary artery smooth muscle cells, and by immunostaining of tissue sections. Results were compared to the same cells cultured under hypoxic conditions.


Within the pulmonary arterial circulation, transgenic vessel wall thickness was increased, particularly in smaller vessels (30–60mm diameter) due to hypertrophy of the smooth muscle layer (mean wildtype vessel thickness:circumference ratio 0.66±0.02, mean transgenic 0.88±0.04, p<0.05). Pulmonary arterial ring responses to direct and receptor-mediated contractile stimuli were reduced in the transgenic animals (in response to endothelin contraction at 10-5M wildtype 1.10mN±0.02, transgenic 0.62±0.12, p<0.05) and right ventricular pressures were elevated in transgenic animals (wildtype mean 29mmHg±4, transgenic mean 37mmHg±3). Explanted transgenic vascular smooth muscle cells showed upregulation of TGFb responsive genes including Vegf and Vegfr1 which were further upregulated in the pulmonary arterial circulation (PASMC) when compared to aortic smooth muscle cells (AoSMC) from the same animals.

Endothelin receptor A gene expression was also reduced in transgenic animals. Hypoxic culture resulted in upregulation of Vegf and Vegfr1 in cells from both wildtype and transgenic animals, again more marked in the pulmonary arterial cells.


The pulmonary vascular phenotype of this transgenic mouse model appears to replicate key histological and patho-physiological features of human SSc, and supports a potential role for perturbed TGFb, endothelin and VEGF activity in the pulmonary circulation in this model.

To cite this abstract, please use the following information:
Derrett-Smith, Emma C., Dooley, Audrey, Baliga, Reshma, Hobbs, Adrian, MacAllister, Raymond, Abraham, David, et al; Perturbed VEGF Signalling within the Pulmonary Vasculature of a TGF Dependent Mouse Model of Systemic Sclerosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :674
DOI: 10.1002/art.28442

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