Genetic Analysis of Murine Chronic Hypoxia-Induced Pulmonary Hypertension

Heterozygous germline mutations, primarily in BMPR2 (with a relatively small number in a few other genes), have been identified in some patients with both the heritable and idiopathic forms of pulmonary arterial hypertension (PAH). Both the lack of identified genetic mutations in all heritable PAH patients (only about 80% of patients with mutations) as well as the reduced penetrance of the disease in those carrying BMPR2 mutations (as low as 20% in some families) suggest that additional genetic factors contribute to the etiology of PAH.

To investigate these additional factors, our lab is using mouse models in an integrative mapping approach:

• First, we have characterized the chronic hypoxia-induced phenotype in 33 different inbred mouse strains by exposing them to 10% O2 for 4 weeks in specialized chambers. Right ventricular systolic pressure (RVSP) was determined via right heart catheterization in a cohort of animals for each strain. The 33 strains were then ordered from low to high based on their RVSP and right ventricle/left ventricle plus septum weight (RV/LV+S) response 9a measure of right ventricular hypertrophy).

• Second, F2 mice were generated by mating high hypoxic responders with low hypoxic responders. These F2 animals were exposed to chronic hypoxia and then phenotyped (RVSP, RV/LV+S, hematocrit) as above. The mice were also genotyped with a SNP panel. The combination of phenotype data and genetic data allowed us to perform conventional QTL mapping for loci that contributed to chronic hypoxia-induced PH.

• Third, lung and right ventricle tissue samples from mouse models showing susceptibility or resistance to hypoxia-induced PH were collected for mRNASeq and miRNASeq in an effort to locate genes that are under or overexpressed in response to hypoxia and may contribute to the development of hypoxia-induced PH.

The goal of this integrative mapping approach is to find overlap in the different approaches and locate genes or loci that are responsible for causing or modifying hypoxia-induced PH.

Funded by:  NHLBI grant, 5R01HL102107