JVS - Vascular Science (Jan 2024)
Hypercholesterolemia impairs collateral artery enlargement by ten-eleven translocation 1-dependent hematopoietic stem cell autonomous mechanism in a murine model of limb ischemia
Abstract
Objective: The extent of collateral artery enlargement determines the risk of limb loss due to peripheral arterial disease. Hypercholesterolemia impairs collateral artery enlargement, but the underlying mechanism remains poorly characterized. This study tests the hypothesis that hypercholesterolemia impairs collateral artery enlargement through a ten-eleven translocation 1 (Tet1)-dependent hematopoietic stem cell (HSC)-autonomous mechanism that increases their differentiation into proinflammatory Ly6Chi monocytes and restricts their conversion into proangiogenic Ly6Clow monocytes. Methods: To test our hypothesis, we induced limb ischemia and generated chimeric mouse models by transplanting HSCs from either wild-type (WT) mice or hypercholesterolemic mice into lethally irradiated WT recipient mice. Results: We found that the lethally irradiated WT recipient mice reconstituted with HSCs from hypercholesterolemic mice displayed lower blood flow recovery and collateral artery enlargement that was nearly identical to that observed in hypercholesterolemic mice, despite the absence of hypercholesterolemia and consistent with an HSC-autonomous mechanism. We showed that hypercholesterolemia impairs collateral artery enlargement by a Tet1-dependent mechanism that increases HSC differentiation toward proinflammatory Ly6Chi monocytes and restricts the conversion of Ly6Chi monocytes into proangiogenic Ly6Clow monocytes. Moreover, Tet1 epigenetically reprograms monocyte gene expression within the HSCs. Restoration of Tet1 expression in HSCs of hypercholesterolemic mice restores WT collateral artery enlargement and blood flow recovery after induction of hindlimb ischemia. Conclusions: These results show that hypercholesterolemia impairs collateral artery enlargement by a novel Tet1-dependent HSC-autonomous mechanism that epigenetically reprograms monocyte gene expression within the HSCs. : Clinical Relevance: The extent of collateral artery enlargement determines the risk of limb loss due to peripheral arterial occlusive disease, survival after acute myocardial infarction, and the occurrence of neurological deficits after ischemic stroke. Yet, the mechanisms that regulate collateral artery enlargement are incompletely characterized. We show that hypercholesterolemia impairs collateral artery enlargement by a hematopoietic stem cell (HSC)-autonomous mechanism where the monocyte number and gene expression are epigenetically reprogrammed within the HSC. Thus, therapeutic agents for peripheral arterial disease should focus on normalizing the immune response during collateral artery enlargement.
