Ketul Chaudhary, Ottawa Hospital Research Institute
Supervisor: Duncan Stewart, Ottawa Hospital Research Institute
Pulmonary arterial hypertension (PAH) is a progressive disease of pulmonary vasculature with unclear etiology. PAH is characterized by increase in mean pulmonary arterial pressure (>25 mmHg) leading to right ventricular hypertrophy and heart failure, and ultimately death. While the pharmacotherapy can slow the progression of the disease, there is no cure. PAH is a multifactorial disease with a strong genetic component. A multitude of environmental factors have also been implicated in PAH; however, the exact pathobiology still remains unclear.
An experimental model that better reproduces the salient pathological features of human PAH, involves the injection a single dose of the VEGFR2 antagonist, SU5416 (SU), followed by a 3-week exposure to chronic hypoxia (CH). Recently, our laboratory has reported strain-specific differences in the rat SU/CH model of severe PAH. We have observed that a specific colony of the Sprague Dawley (SD) rats (Charles River Labs, Canada) is hyper-responsive (HR) to SU. These rats developed progressive severe PAH in response to a single SU injection, even in absence of CH. The HR phenotype was seen in ~70% of the male rats and only in ~30% of the female rats. Furthermore, crossing non-responsive male and female animals decreased the proportion of HR animals in the F1 generation (male: 15%; female: 0%), consistent with genetic basis for the HR phenotype. Ongoing studies in our lab, using whole exome sequencing, have discovered unique mutations that are not found in 40 other rat strains. The candidate genes with mutations are the hypoxia inducible factor-1α (Hif1α), cingulin like-1 (CGNL1), pituitary tumor transforming growth factor-1 (PTTG1) and SP110. The homozygous mutation in Hif1α was present in 80% of rats from this colony, while remaining 20% were heterozygous mutant. In the proposed project, we will investigate the role of these unique mutations and female sex hormones in the vascular remodeling and HR phenotype. Hypothesis: We hypothesize that hyper-responsiveness to SU alone is conferred by unique genetic determinant(s). Moreover, the influence of this genetic determinant(s) is importantly modified in a sex-dependent manner, likely by the action of female sex hormones. AIMs: 1) Study the role of Hif1α and other candidate genes in vascular remodeling and HR phenotype. 2) Investigate the effect of female sex hormones on endothelial cell apoptosis, vascular remodeling and HR phenotype.
This work may uncover novel genetic factors that cause susceptibility of the pulmonary endothelial cells to apoptosis and vascular remodeling, leading to severe PAH phenotype, and could also be involved in development and/or progression of PAH in human patients. Further, this work could also explain the protective effects of female sex hormones in development and/or progression of PAH in this unique model. Overall, the project will provide insight into the pathobiology of PAH and provide novel therapeutic targets for the curative treatment of this devastating incurable vascular disease. Pulmonary hypertension is one of the priority research areas of the vascular network and the proposed project is directly related to the opportunity.