Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension

Abstract

SUMMARY Pulmonary hypertension is a devastating disease characterized by excessive vascular muscularization. We previously demonstrated primed platelet-derived growth factor receptor β+ (PDGFR-β+)/smooth muscle cell (SMC) marker+ progenitors at the muscular-unmuscular arteriole border in the normal lung, and in hypoxia-induced pulmonary hypertension, a single primed cell migrates distally and expands clonally, giving rise to most of the pathological smooth muscle coating of small arterioles. Little is known regarding the molecular mechanisms underlying this process. Herein, we show that primed cell expression of Kruppel-like factor 4 and hypoxia-inducible factor 1-α(HIF1-α) are required, respectively, for distal migration and smooth muscle expansion in a sequential manner. In addition, the HIF1-α/PDGF-B axis in endothelial cells non-cell autonomously regulates primed cell induction, proliferation, and differentiation. Finally, myeloid cells transdifferentiate into or fuse with distal arteriole SMCs during hypoxia, and Pdgfb deletion in myeloid cells attenuates pathological muscularization. Thus, primed cell autonomous and non-cell autonomous pathways are attractive therapeutic targets for pulmonary hypertension.

HIF Oxygen Sensing Pathways in Lung Biology

“…Surprisingly, the attenuation of vascular remodeling and PH was not reflected by an attenuation of right ventricle cardiac hypertrophy, which is in line with previous data showing that increased PH might not fully explain right heart failure [ 27 , 28 ]. An additional study has used Pdgfrb-CreERT2 mice in order to inactivate Hif1a in previously identified pulmonary PDGFRβ + /αSMC + progenitors that are primed in hypoxia-induced PH [ 29 , 30 ]. These mice show that distal arterioles are less covered by α-smooth muscle positive cells and a profound attenuation of PH and right ventricular hypertrophy [ 29 ].…”

“…An additional study has used Pdgfrb-CreERT2 mice in order to inactivate Hif1a in previously identified pulmonary PDGFRβ + /αSMC + progenitors that are primed in hypoxia-induced PH [ 29 , 30 ]. These mice show that distal arterioles are less covered by α-smooth muscle positive cells and a profound attenuation of PH and right ventricular hypertrophy [ 29 ]. The differences between these two studies can arise by the different Cre lines employed.…”

Specialized Smooth Muscle Cell Progenitors in Pulmonary Hypertension

“…In contrast to KLF4, our studies suggest that HIF1-α in PDGFR-β + cells is not required for initial primed cell migration but is needed for the subsequent clonal expansion. In ECs, HIF1-α is upstream of PDGF-B, and EC deletion of either of these genes non-cell autonomously attenuates hypoxia-induced primed cell KLF4 expression, distal muscularization and PH [7,13].…”

Hot topics in the mechanisms of pulmonary arterial hypertension disease: cancer‐like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure

“…119 Deletion of HIF1a or PDGFR in ECs results in decreased SMC expansion and ameliorated PH. 120 In this study, the authors additionally provide the sequence of events leading to vascular remodeling in their PH model. In the initiation phase (days 1-3 of hypoxia), expression of HIF1a and PDGFR in ECs induces Kru¨ppel Like Factor 4 (KLF4) expression in primary PASMCs and their migration.…”