TSC2-extracellular matrix crosstalk controls pulmonary vascular proliferation and pulmonary hypertension
biorxiv(2021)
摘要
Increased proliferation and survival of resident cells in small pulmonary arteries (PA) are important drivers of pulmonary hypertension (PH). Tuberous sclerosis complex 2 (TSC2) is a negative regulator of mTOR complex 1 and cell growth. Here we show that TSC2 is deficient in small remodeled PA/PA vascular smooth muscle cells (PAVSMC) from human PAH and experimental PH lungs. TSC2 deficiency was reproduced in vitro by maintaining PAVSMC on pathologically stiff substrates and was required for stiffness-induced proliferation, accumulation of transcriptional co-activators YAP/TAZ and up-regulation of mTOR. Depletion of TSC2 reproduced PH features in vitro in human PAVSMC and in vivo in SM22-Tsc2+/− mice. TSC2 loss in PAVSMC was supported by YAP and led to the up-regulation of YAP/TAZ and mTOR via modulating the extracellular matrix (ECM) composition. ECM, produced by TSC2-deficient PAVSMC, promoted growth of non-diseased PA adventitial fibroblasts and PAVSMC, which, in turn, was prevented by α5β1 integrin receptor antagonist ATN161. In vitro , molecular and pharmacological (SRT2104) restoration of TSC2 down-regulated YAP/TAZ, mTOR, and ECM production, inhibited proliferation and induced apoptosis in human PAH PAVSMC. In vivo , orally administrated SRT2104 restored TSC2, resolved pulmonary vascular remodeling, PH, and improved right heart in two rodent models of PH. Thus, PAVSMC TSC2 is a critical integrator of ECM composition and stiffness with pro-proliferative signaling and PH, and the restoration of functional TSC2 could be an attractive therapeutic option to treat PH.
One Sentence Summary TSC2 acts as mechanosensor and mechanotransducer, integrating ECM composition and stiffness with pro-proliferative signaling in pulmonary vasculature; its deficiency in PA vascular smooth muscle cells results in ECM remodeling, hyper-proliferation and pulmonary hypertension, which could be reversed by pharmacological restoration of functional TSC2.
### Competing Interest Statement
The authors have declared no competing interest.
* BrdU
: Bromodeoxyuridine
BSA
: Bovine serum albumin
Col1A1
: Collagen 1A1
DAPI
: 4’,6-diamidino-2-phenylindole
ECM
: Extracellular matrix
ET-1
: Endotelin-1
FN
: Fibronectin
GFP
: Green fluorescent protein
H&E
: Hematoxylin and eosin
IGF-1
: Insulin growth factor 1
IL-6
: Interleukin-6
IPAH
: Idiopathic pulmonary arterial hypertension
LAM
: Lymphangioleiomyomatosis
LV
: Left ventricular/ventricle
MAP
: Mean arterial pressure
mTOR
: Mechanistic target of rapamycin
mTORC
: Mechanistic target of rapamycin complex
PA
: Pulmonary artery
PA MT
: Pulmonary artery medial thickness
PAAF
: Pulmonary artery adventitial fibroblast
PAEC
: Pulmonary artery endothelial cell
PAH
: Pulmonary arterial hypertension
PAP
: PA pressure
PAVSMC
: Pulmonary artery vascular smooth muscle cells
PDGF-BB
: Platelet-derived growth factor-BB
PH
: Pulmonary hypertension
RV
: Right ventricular/ventricle
SIRT1
: Sirtuin 1
sLVP
: Systolic left ventricular pressure
SM22
: Smooth muscle protein 22-alpha
SMA
: Smooth muscle a-actin
sRVP
: Systolic right ventricular pressure
SuHx
: SU5416/Hypoxia
TNF-α
: Tumor necrosis factor-a
TSC2
: Tuberous sclerosis complex 2
TUNEL
: Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling
WT
: Wild type
YAP
: Yes-associated protein
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关键词
pulmonary hypertension,vascular proliferation
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