Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.

Intermittent Systemic VEGF Inhibition Induces Pulmonary Arterial Hypertension In a Transgenic Mouse Model of Scleroderma.

Derrett-Smith1,  Emma, Dooley1,  Audrey, Baliga2,  Reshma, Hobbs2,  Adrian, Abraham3,  David J., Denton1,  Christopher P.

UCL Medical School, London, United Kingdom
Centre for Cardiovascular Pharmacology, University College London, London, United Kingdom
Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, London, United Kingdom


Pulmonary arterial hypertension (PAH) is a major complication in ~15% of SSc cases and occurs throughout the disease suggesting that a second vascular event occurring in the context of a systemic disease may be responsible. We have previously shown that a transgenic mouse model develops many features of SSc including susceptibility to systemic vasculopathy and lung fibrosis. A role for altered VEGF signaling in PAH-SSc is supported by data that correlate circulating VEGF with mPAP at diagnosis. High circulating VEGF levels may be a marker of repair in response to vascular injury. VEGF signaling is upregulated in the TbRIIDk-fib mouse model of SSc, which has evidence of a constitutive pulmonary vasculopathy. We have inhibited VEGF signaling using SU5416 to induce endothelial apoptosis in this model.


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. The constitutive pulmonary vasculopathy was confirmed by histological assessment of vessel architecture, isolated organ bath and in vivo haemodynamic studies. Biochemical analysis of the VEGF signaling axis by quantitative PCR and Western blotting was performed using cultured pulmonary artery smooth muscle cells, and by immunostaining of tissue sections. In vivo SU5416 administration to transgenic and wildtype animals was compared to vehicle administration alone (n=6 each group). Post mortem RV mass index measurements were taken, and histological and immunohistochemical stains (H&E, SR, CD31) were performed.


Within the transgenic pulmonary arterial circulation, hypertrophy of the smooth muscle layer was increased (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, p<0.05). Explanted transgenic PASMC showed upregulation of VEGF and VEGFR1. RV mass index in transgenic animals was increased after treatment with SU5416 (transgenic, vehicle only 0.19±0.01, SU5416 treated 0.29±0.03, p<0.05). Histological and immunohistochemical analysis revealed evidence of obliterative endothelial proliferation in transgenic SU5416 treated animals similar to human plexiform lesions which was not seen in any other group.


Treatment with SU5416 exacerbates the underlying constitutive pulmonary vascular defect of this transgenic mouse model and replicates the key histological and patho-physiological features seen in human PAH-SSc. These findings support a role for perturbed TGFb and VEGF activity in the pulmonary circulation in SSc, supporting the concept of a second pulmonary endothelial injury leading to PAH in SSc. This model may provide a valuable platform for future therapeutic studies in vivo as well as providing insight into pathogenic mechanisms.

To cite this abstract, please use the following information:
Derrett-Smith, Emma, Dooley, Audrey, Baliga, Reshma, Hobbs, Adrian, Abraham, David J., Denton, Christopher P.; Intermittent Systemic VEGF Inhibition Induces Pulmonary Arterial Hypertension In a Transgenic Mouse Model of Scleroderma. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2603

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