Elucidation of the mechanism of initiation and progression of pulmonary artery lesions caused by pathological high shear stress and its therapeutic application

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15948
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagoya City University
• Principal Investigator: Shinohara Tsutomu 名古屋市立大学, 医薬学総合研究院(医学), 助教 (50745932)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 肺高血圧 / シェアストレス / 内皮間葉転換 / ERG / 左右短絡マウス

Outline of Final Research Achievements

High shear stress (HSS) induced endothelial to mesenchymal transition (EndMT), as assessed by decreased endothelial cell (EC) markers, and increased　mesenchymal markers. The transcription factor ERG was reduced with HSS. Indeed　ERG siRNA under LSS caused EndMT whereas under HSS, transfection of ERG　prevented EndMT. We created an aortocaval (AV) shunt in mice and compared PAH in those sham operated vs transfected with an adeno-associated viral vector selectively targeting PAEC with a luciferase (control) or an ERG expressing construct. Eight weeks after AV shunt, right ventricular systolic pressures was 21.9 ±0.6 mmHg in sham, 37.2±1.0 mmHg in AV shunt with luciferase vector and 29.2±0.8 mmHg in ERG-vector.
Our study is the first to document pathological HSS as an inducer of EndMT and PAH and to show that this results from reduced pulmonary artery EC ERG.

Free Research Field

Pulmonary Hypertension

Academic Significance and Societal Importance of the Research Achievements

肺動脈性肺高血圧症の治療薬は血管拡張・収縮物質産生の不均衡理論に基づいている。しかしすでに病期の進行した症例においては治療抵抗性を指摘する数多くの報告がなされている。そこで本研究は、シミュレーション医学によって見出された、肺血管病変部に生じる病的高シェアストレスに焦点を当てた、血管リモデリングの機序の解明と新たな治療ターゲットを同定すことを目的として行った。肺循環の血管リモデリングの機序を病的高シェアストレス刺激に着目し、転写因子ERGの低下により内皮間葉転換が起こることを見出した本研究は独自性が非常に高く、新たな抗リモデリング治療のターゲットに繋がる可能性を秘めており、創造性が極めて高い。