Rationale: Hypercholesterolemia has been verified as an important risk factor of cardiovascular diseases. It has been shown to impair the post-ischemic arteriogenesis, the major physiological process in response to ischemic injury. As yet, the underlying mechanism is not fully illustrated. Objective: Our own data indicate that hematopoietic stem cells (HSCs) functions as a determinant in post-ischemic arteriogenesis by differentiating into vascular progenitors. However, the differentiation processes and the underlying mechanisms remain unknown. Ten eleven translocation (Tet) family are a group of enzymes initiating the demethylation of DNA. Tet1 is specifically downregulated in HSCs from hypercholesterolemic mice. Therefore, we hypothesized that Tet1 regulates the differentiation from HSCs towards vascular progenitors. Hypercholesterolemia reduces vascular specification of HSCs through a Tet1 dependent epigenetic pathway. Methods and Results: The ex vivo differentiation and in vivo transplantation experiments showed that HSC-originated Ly6C low monocytes in peripheral blood possess the greatest capacity to differentiate into vascular cells and to improve the post-ischemic arteriogenesis. Ly6C low monocyte population was specifically reduced in Tet1 -/- mice after the induction of hindlimb ischemia, consequently resulting in significant impairment of post-ischemic arteriogenesis. Tet1 deficiency caused unique expression profiles of the genes involved in the differentiation of HSCs towards monocytes. RT-PCR showed that the expression of Tet1 was specifically downregulated in HSCs isolated from ApoE -/- mice. As expected, the Ly6C low monocyte population was specifically reduced and the post-ischemic arteriogenesis was significantly impaired in ApoE -/- mice. Conclusion: Ly6C low monocytes are the major vascular progenitors originated from HSCs. Tet1 dependent epigenetic regulation is critical in the differentiation process from HSCs towards Ly6C low monocytes. Hypercholesterolemia inhibits the expression of Tet1 and subsequently impairs the differentiation from HSCs towards Ly6C low monocytes, resulting in the impairment of post-ischemic arteriogenesis.