SOX17 at the Intersection of Sex, Transcription, and Metabolism in Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is an incurable and devastating disease characterized by pulmonary vascular remodeling, increased pulmonary vascular resistance, and right heart failure. Genetic mutations account for 23.5% of PAH cases (1). Among known mutations, there is considerable genetic heterogeneity from a diverse collection of rare heterozygous coding-region mutations. One such genetic mutation affects SOX17 (SRY-related HMG-box17) (1). SOX17 is a key endothelial-specific transcription factor involved in angiogenesis (2), induction of tip cell differentiation (3), arteriovenous differentiation (4), and pulmonary endothelial regeneration following vascular injury (5). PAH secondary to deleterious SOX17 variants is associated with congenital heart disease (6) and clinically presents with severe hemodynamic derangements (mean pulmonary arterial pressure of 67 mm Hg and pulmonary vascular resistance of 14.0 Wood units) (7).

Recently, a common genetic variant in the enhancer region of SOX17 was found through a genome-wide association study in an international cohort of patients with PAH (8). This discovery raised the question of the contribution of SOX17 as a risk allele for PAH.

In this issue of the Journal, Sangam and colleagues (pp. 1055–1069) proposed that SOX17 deficiency promotes PAH through interactions with hypoxia-inducible factor 2α (HIF2α) and estrogen pathways, as well as dysfunctional mitochondrial metabolism (9). The authors first noted decreased endothelial-specific SOX17 expression in human pulmonary artery endothelial cells isolated from patients with PAH and in rats with chronic hypoxia-induced pulmonary hypertension (PH) and monocrotaline PH. Using an inducible conditional Tie2-Sox17 knockout murine model, the authors found that exposure of Sox17-deficient mice to hypoxia resulted in pulmonary vascular remodeling, increased right-sided pressure, and right ventricular hypertrophy. Conversely, Sox17-transgenic overexpression in mice attenuated hypoxic PH development. Next, the authors demonstrated that Sox17 serves a protective function in the regulation of HIF2α expression and subsequent promotion of normal mitochondrial function in Sox17-deficient mice. In vitro studies of SOX17 adenovirus-facilitated overexpression in pulmonary artery endothelial cells resulted in enhanced mitochondrial bioenergetics with increased trichloroacetic acid cycle intermediates. This effect, however, was reversed by the concurrent overexpression of SOX17 and HIF2α. As such, this study adds to the existing body of literature on the pivotal role of HIF2α signaling in PH (a comprehensive review on this topic is provided by Pullamsetti and colleagues [10]). Further work is needed to fully elucidate the mechanism between SOX17 and endothelial HIF2α.

Finally, the authors explored the role of estrogen-mediated transcriptional regulation of SOX17 in murine models. Through in vitro and in vivo approaches, the authors found an inverse relationship between estrogen metabolite 16αOHE and SOX17 levels in PAH. However, Sox17 only partially attenuated 16αOHE-mediated murine PH, suggesting additional mechanisms in estrogen-mediated PH. Nevertheless, these studies implicate SOX17-mediated sex-dependent differences in PAH susceptibility. On the basis of these current findings, Sangam and colleagues were able to postulate a new link between SOX17 and estrogen-mitochondrial function.

The elegant studies by Sangam and colleagues contribute new knowledge on how estrogen and its metabolites affect SOX17-deficient PAH. Their findings have larger implications given the “estrogen paradox” of PAH whereby sex affects disease penetrance, presentation, progression, and mortality (11). Further work, however, is required to fully elucidate the mechanisms contributing to the pathogenesis of PAH secondary to SOX17. This task is challenging given the limitations in the use of experimental animal models and the difficulties in recapitulating complex human diseases. Moreover, the regulation of SOX17 activity is complex, as SOX17 interacts with transcriptional targets involved in multiple signaling pathways of clinical relevance to PAH, including Notch, TGF-β, Wnt/β-catenin, and HGF/c-Met signaling pathways (12, 13). In tackling this challenge, studies such as the one performed by Sangam and colleagues offer new insights into the molecular pathways underlying genetic variants and illustrate the importance of common genetic variants as potential new therapeutic targets.