Fig. 1.The mechanism underlying pericyte transformation into
myofibroblasts. (a) transforming growth factor- (TGF-)
production was increased (damaged epithelial cells produce TGF-;
toll-like receptor 4 (TLR-4) and TGF- were highly expressed in pericytes
upon lipopolysaccharide (LPS) induction; and Sirtuin 3 (SIRT3) highly expresses
TGF- by increasing reactive oxygen species (ROS) levels), and then
TGF- with receptor phosphorylation, multiple downstream adjustment
factor is activated (e.g., Smad2/3 signaling, and non-Smad pathways).
Phosphorylated TGF- promotes the phosphorylation of Smad2/3 and
extracellular regulated protein kinase 1 (ERK1), leading to
pericyte-myofibroblast transition (PMT). Phosphorylated Smad2/3 (P-Smad2/3)
translocated to the nucleus, and the accumulation of P-Smad2/3 in the nucleus
increases the binding to Smad-binding elements (SBE), leading to increased
transcription of fibrotic genes, which in turn increases matrix proteins
(including collagen type I) leading to increased extracellular matrix (ECM)
deposition. Binding of FAK to the ECM leads to increased translocation of MKL-1,
yes-associated protein (YAP), and transcriptional coactivators with PDZ-binding
motifs (TAZ), which in turn lead to increased -SMA expression and
myofibroblast transition, leading to idiopathic pulmonary fibrosis (IPF). (b)
Notch1 and exogenous bleomycin can regulate platelet-derived growth factor
receptor (PDGFR) activity, and PDGFR activation can regulate a variety of
downstream signaling molecules, such as Ras, phosphatidylinositol 3-Kinase (PI3K)
and phospholipase C (PLC). In addition, PDGFR also regulates Rho-related protein
kinase 1 (ROCK1), which is involved in the pathogenesis of pulmonary fibrosis,
while PDGF signaling can stimulate ERK1/2 activation in pericytes. (c)
Macrophages can modulate the vascular endothelial growth factor (VEGF) /PI3K
pathway through the gasdermin D (GSDMD)/ interleukin-1 (IL-1)
axis, thereby altering the transition of pericytes to fibrosis. (d)
damage-associated molecular patterns (DAMPs) occur when cells are damaged, bind
to receptors TLR2/4 on pericytes, induce changes in MyD88 and interleukin-1
receptor associated kinase 4 (RAK4) signaling and develop pulmonary fibrosis. (e)
The mTOR is a member of the phosphatidylinositol-3-OH-kinase-related family,
TGF- binds to its receptor and activates Akt/mTOR
signaling pathway to mediate the proliferation of ECM and PMT.