Endothelial Cell-Specific Prolyl Hydroxylase-2 Deficiency Augments Angiotensin II-Induced Arterial Stiffness and Cardiac Pericyte Recruitment in Mice.
J Am Heart Assoc
; 13(16): e035769, 2024 Aug 20.
Article
en En
| MEDLINE
| ID: mdl-39056332
ABSTRACT
BACKGROUND:
Endothelial prolyl hydroxylase-2 (PHD2) is essential for pulmonary remodeling and hypertension. In the present study, we investigated the role of endothelial PHD2 in angiotensin II-mediated arterial stiffness, pericyte recruitment, and cardiac fibrosis. METHODS ANDRESULTS:
Chondroitin sulfate proteoglycan 4 tracing reporter chondroitin sulfate proteoglycan 4- red fluorescent protein (DsRed) transgenic mice were crossed with PHD2flox/flox (PHD2f/f) mice and endothelial-specific knockout of PHD2 (PHD2ECKO) mice. Transgenic PHD2f/f (TgPHD2f/f) mice and TgPHD2ECKO mice were infused with angiotensin II for 4 weeks. Arterial thickness, stiffness, and histological and immunofluorescence of pericytes and fibrosis were measured. Infusion of TgPHD2f/f mice with angiotensin II resulted in a time-dependent increase in pulse-wave velocity. Angiotensin II-induced pulse-wave velocity was further elevated in the TgPHD2ECKO mice. TgPHD2ECKO also reduced coronary flow reserve compared with TgPHD2f/f mice infused with angiotensin II. Mechanistically, knockout of endothelial PHD2 promoted aortic arginase activity and angiotensin II-induced aortic thickness together with increased transforming growth factor-ß1 and ICAM-1/VCAM-1 expression in coronary arteries. TgPHD2f/f mice infused with angiotensin II for 4 weeks exhibited a significant increase in cardiac fibrosis and hypertrophy, which was further developed in the TgPHD2ECKO mice. Chondroitin sulfate proteoglycan 4 pericyte was traced by DsRed+ staining and angiotensin II infusion displayed a significant increase of DsRed+ pericytes in the heart, as well as a deficiency of endothelial PHD2, which further promoted angiotensin II-induced pericyte increase. DsRed+ pericytes were costained with fibroblast-specific protein 1 and α-smooth muscle actin for measuring pericyte-myofibroblast cell transition. The knockout of endothelial PHD2 increased the amount of DsRed+/fibroblast-specific protein 1+ and DsRed+/α-smooth muscle actin+ cells induced by angiotensin II infusion.CONCLUSIONS:
Knockout of endothelial PHD2 enhanced angiotensin II-induced cardiac fibrosis by mechanisms involving increasing arterial stiffness and pericyte-myofibroblast cell transitions.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fibrosis
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Angiotensina II
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Ratones Noqueados
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Pericitos
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Células Endoteliales
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Rigidez Vascular
Límite:
Animals
Idioma:
En
Revista:
J Am Heart Assoc
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Reino Unido