Elucidating the original cell and mechanism of aortic valve ectopic calcification and developing new drugs for inhibiting calcification

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16381
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55030:Cardiovascular surgery-related
• Research Institution: Hirosaki University
• Principal Investigator: YU ZAIQIANG 弘前大学, 医学研究科, 客員研究員 (40624268)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 大動脈弁石灰化 / 大動脈弁狭窄症 / 薬物治療

Outline of Final Research Achievements

Aortic valve stenosis (AVS) is accompanied by irreversible calcification without medical therapy. We recently demonstrated that human aortic valve interstitial cells (HAVICs) obtained from AVS patients were highly sensitive to ectopic calcification stimulation, The immunohistochemical features of HAVICs were analyzed. Cultured P1 HAVICs were CD73-, CD90-, and CD105-positive, and CD45- and CD34-negative. HAVICs were vascular endothelial growth factor receptor 2 (VEGFR2)-positive; however, approximately half were α-smooth muscle actin (SMA)-positive, colonized, and easily differentiated into osteoblastic cells. Calcified aortic valve immunohistochemistry showed that all cells were positive for VEGFR2 but partly α-SMA. VEGFR2-positive cells were more sensitive to tumor necrosis factor-α-induced ectopic calcification. We conclude that HAVICs obtained from patients with AVS are VEGFR2-positive undifferentiated mesenchymal cells and may contribute to aortic valve ectopic calcification.

Free Research Field

心臓血管外科学

Academic Significance and Societal Importance of the Research Achievements

VEGFR2陽性細胞は、AVS患者から得た大動脈弁において、内皮だけでなく間質にも多数局在していたため、AVS患者から単離されたHAVICsが大動脈弁内皮細胞に由来し、例えば、内皮間葉移行によるこれらの細胞の分化が大動脈弁の異所性石灰化に寄与する可能性があることを示唆している。これらの結果に基づいて、内皮間葉移行を視野に据えた大動脈弁異所性石灰化のメカニズムを解明し、AVS増悪の主要因である異所性石灰化の進行を抑制するための新しい治療法を開発する必要がある。今後の弁石灰化の機序を解明するとともに、弁石灰化の進行を抑制する薬物治療法の開発には新しい治療ターゲットを提供した重要な意義がある。