mTORC1 in Pulmonary Arterial Hypertension. At the Crossroads between Vasoconstriction and Vascular Remodeling?

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease with no cure. Pulmonary arterial pressure (PAP) is a function of cardiac output and pulmonary vascular resistance (PVR). In patients with PAH, the increased PAP is mainly due to increased PVR. The major causes for the elevated PVR and PAP are sustained pulmonary vasoconstriction, concentric pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular wall stiffness. Current therapies, however, target mainly vasoconstriction, and despite the advent of 14 medical therapies across three vasodilation pathways (prostacyclin, nitric oxide, and endothelin-1), the disease remains severe and life threatening. Pulmonary vascular remodeling is caused, at least in part, by increased proliferation and/or survival of resident pulmonary vascular cells, and antiproliferative/proapoptotic strategies are now under development as disease-modifying therapies for PAH. Yet the mechanisms for vasoconstriction (and/or vasodilation) and vascular remodeling are not entirely separate. Drugs that are effective for treatment of PAH may attenuate pulmonary vasoconstriction and also inhibit pulmonary vascular remodeling. One of the therapeutic examples is prostacyclin or its chemically stable analog, treprostinil, a potent vasodilator that is currently in use for the treatment of PAH. It has been noted that, in addition to its vasodilatory effect, prostacyclin or treprostinil, when given in high doses, attenuates experimental pulmonary hypertension (PH) by inhibiting proliferation of pulmonary artery smooth muscle cells (PASMCs). Interestingly, in addition to canonical activation of the EP 2 (prostaglandin E2 receptor 2) and the PPAR-g (peroxisome proliferator-activated receptor-g), prostacyclin inhibits cell proliferation induced by PDGF (platelet-derived growth factor) and transforming growth factor b, suggestive of EP 2-independent mechanisms of action (1-3). In this issue of the Journal, He and colleagues (pp. 1263-1276) uncover another enticing link between the vasodilatory prostacyclin axis and antiproliferative signaling in the pulmonary vasculature (4). The authors demonstrate that DP1 (D prostanoid receptor subtype 1), for which treprostinil acts as an agonist, is downregulated in PASMCs from patients with PAH and animals with experimental PH. Intriguingly, DP1 deficiency exacerbated pulmonary artery (PA) remodeling in mice with hypoxia-induced PH via activation of the mTOR (mechanistic target of rapamycin) complex 1 (mTORC1) (Figure 1). The mTOR, a fundamental regulator of cellular homeostasis, acts through two functionally This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.

Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells

“…The PI3K/AKT/mTOR signaling cascade is a major signaling pathway involved in cell proliferation and protein synthesis in a variety of cell types including cancer cells and PASMCs (Goncharov et al, 2014;Sahoo et al, 2016;Meng et al, 2017;Babicheva et al, 2021). Our lab and other investigators have reported that the PI3K/AKT1/mTORC1/C2 pathways are involved in the development and progression of experimental PH in mice (Tang et al, 2015(Tang et al, , 2018bGoncharova et al, 2020). The next set of experiments was designed to investigate whether the transition of PASMCs from the contractile (isolated PA) to proliferative (primary cultured PASMC) phenotype requires upregulation or activation of the signaling proteins involved in the PI3K/AKT/mTOR pathway.…”

“…The mTOR complex 1 (mTORC1) and mTORC2 play important roles in the regulation of cell proliferation and protein expression, while both complexes are involved in the development and progression of PH ( Houssaini et al, 2013 , 2016 ; Goncharov et al, 2014 ; Lee et al, 2016 ; Guo et al, 2019 ; Goncharova et al, 2020 ; Babicheva et al, 2021 ). PASMCs in the normal PA exhibit a differentiated, quiescent, and contractile phenotype.…”

Topic-Based, Recent Literature Review on Pulmonary Hypertension

“…One area of focus is the bridge between vasoconstriction and vascular remodeling. 2,3 Medications that vasodilate may also inhibit pulmonary vascular remodeling; therefore, an understanding of the basic mechanisms potentially identifies additional treatment targets. As such, He et al 3 examined pulmonary arteries from both patients and animals, thereby linking the action of prostanoids on D prostanoid receptor subtype 1 and the induction of mammalian target of rapamycin (mTOR) complex 1.…”

Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension

“…Prior studies have shown that mTORC1 inhibition with rapamycin attenuates pre-clinical PAH development ( Houssaini et al, 2013 ; Goncharova et al, 2020 ). Furthermore, deletion of tuberous sclerosis complex ½ (TSC 1/2), which is an upstream inhibitor of mTORC1 signaling, also inhibits expression of PDGFRs in a rapamycin-sensitive manner ( Zhang et al, 2007 ).…”