Novel signaling pathways in pulmonary arterial hypertension (2015 Grover Conference Series)

Abstract

The proliferative endothelial and smooth muscle cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Mutations in bone morphogenetic protein type 2 receptor (BMPR2) have been identified as the most common genetic cause of PAH and females with BMPR2 mutations are 2.5 times as likely to develop heritable forms of PAH than males. Higher levels of estrogen have also been observed in males with PAH, implicating sex hormones in PAH pathogenesis. Recently, the estrogen metabolite 16α-OHE1 (hydroxyestrone) was implicated in the regulation of miR29, a microRNA involved in modulating energy metabolism. In females, decreased miR96 enhances serotonin's effect by upregulating the 5-hydroxytryptamine 1B (5HT1B) receptor. Because PAH is characterized as a quasi-malignant disease, likely due to BMPR2 loss of function, altered signaling pathways that sustain this cancer-like phenotype are being explored. Extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinases (MAPKs) play a critical role in proliferation and cell motility, and dysregulated MAPK signaling is observed in various experimental models of PAH. Wnt signaling pathways preserve pulmonary vascular homeostasis, and dysregulation of this pathway could contribute to limited vascular regeneration in response to injury. In this review, we take a closer look at sex, sex hormones, and the interplay between sex hormones and microRNA regulation. We also focus on MAPK and Wnt signaling pathways in the emergence of a proproliferative, antiapoptotic endothelial phenotype, which then orchestrates an angioproliferative process of vascular remodeling, with the hope of developing novel therapies that could reverse the phenotype.

Keywords: Wnt; microRNA; mitogen-activated protein kinase; sex hormones; vascular remodeling.

Figure 1

Summary of estrogen (E2) synthesis and metabolic pathways of key interest. See text for details. COMT: catechol-O-methyltransferase; CYP: cytochrome P450; HSD: hydroxysteroid dehydrogenase; OHE1: hydroxyestrone.

Figure 2

Mitogen-activated protein kinase (MAPK) signaling pathways. Simplified schematic depicting the activation of ERK1/2 (extracellular signal-regulated kinases), JNK (c-Jun NH2-terminal kinase), and p38 MAPK after growth factor–, cytokine-, and/or environmental stress–mediated phosphorylation of MAP3 kinases (MAP3K) followed by the phosphorylation and activation of MAP2 kinases (MAP2K). Growth factor–induced receptor tyrosine kinase (RTK) activation results in the subsequent activation of the Raf/MEK/ERK pathway. Growth factors can also mediate the activation of JNK through hematopoietic progenitor kinase (HPK), which phosphorylates MKK4 (mitogen-activated protein kinase kinase 4). Stress-dependent activation of ASK1 (apoptosis signal regulating kinase 1) also targets the MKK4/JNK pathway in addition to MKK3/p38 MAPK. TGFBR1 (transforming growth factor beta receptor 1)-induced activation of TAK1 (TGF-β-activated kinase 1) and ultraviolet radiation–induced RAC1 and/or CDC42 activation results in the activation of both JNK and p38 MAPK.

Figure 3

The Wnt signaling pathways regulate gene expression and cell movements. The Wnt/βC pathway (A) controls gene expression through DVL-dependent activation and nuclear shuttling of βC, while Wnt/PCP (B) modulates motility, polarity, and tissue morphogenesis thru DVL activation of RhoA/Rac1/cdc42. Specific domains within Dvl are responsible for differentia activation of βC (DIX) or PCP (PDZ/DEP). βC: β-catenin; DVL: protein disheveled; FZD: frizzled family of receptors; GSK3: glycogen synthase kinase 3; LRP: low-density lipoprotein receptor–related protein; PCP: planar cell polarity; ROR2: receptor tyrosine kinase-like orphan receptor 2.

Figure 4

Proposed role of Wnt signaling in pulmonary vascular homeostasis. A, Wnt/βC and Wnt/PCP coordinate endothelial growth and movement during vascular repair in response to injury. B, Loss of Wnt signaling results in impaired angiogenesis and is permissive to PASMC-driven obliterative vasculopathy. βC: β-catenin; PASMC: pulmonary artery smooth muscle cell; PCP: planar cell polarity.