Background Hematopoiesis originates from the dorsal aorta during embryogenesis. While adult blood vessels harbor progenitor populations for endothelial and smooth muscle cells, it is not known if they contain hematopoietic progenitor (HPCs) or stem cells (HSCs). Here, we hypothesized that the arterial wall is a source of HPCs and HSCs in postnatal life. Methods and Results Single cell aortic disaggregates were prepared from adult chow-fed C57BL/6 and ApoE−/− mice. In short- and long-term methylcellulose-based culture, aortic cells generated a broad spectrum of multipotent and lineage-specific hematopoietic colony-forming units (CFUs), with preponderance of macrophage CFUs (CFU-M). This clonogenicity was higher in lesion-free ApoE−/− mice and primarily localized to Sca-1+ cells in the adventitia. Expression of Sca-1 in the aorta co-localized with canonical HSC markers, as well as CD45 and mature leukocyte antigens. Adoptive transfer of labeled aortic cells from GFP transgenic donors to irradiated C57BL/6 recipients confirmed content of rare HSCs (1 per 4,000,000 cells), capable of self-renewal and durable, low level reconstitution of leukocytes. Moreover, the predominance of long-term macrophage precursors was evident by late recovery of GFP+ colonies from recipient bone marrow and spleen that were exclusively CFU-M. Although trafficking from bone marrow was shown to replenish some of the aorta’s hematopoietic potential following irradiation, the majority of macrophage precursors appeared to arise locally, suggesting long-term residence in the vessel wall. Conclusions The postnatal murine aorta contains rare multipotent HPCs/HSCs and is selectively enriched with Sca-1+ monocyte/macrophage precursors. These populations may represent novel, local vascular sources of inflammatory cells.

The fundamental contributions that blood vessels make toward organogenesis and tissue homeostasis are reflected by the considerable ramifications that loss of vascular wall integrity has on pre-and postnatal health. During both neovascularization and vessel wall remodeling after insult, the dynamic nature of vascular cell growth and replacement vitiates traditional impressions that blood vessels contain predominantly mature, terminally-differentiated cell populations. Recent discoveries have verified the presence of diverse stem/progenitor cells for both vascular and non-vascular progeny within the mural layers of the vasculature. During embryogenesis, this encompasses the emergence of definitive hematopoietic stem cells and multipotent mesoangioblasts from the developing dorsal aorta. Ancestral cells have also been identified and isolated from mature, adult blood vessels, showing variable capacity for endothelial, smooth muscle, hematopoietic and mesenchymal differentiation. At present, the characterization of these different vascular wall progenitors remains somewhat rudimentary, but there is evidence for their constitutive residence within organized compartments in the vessel wall, most compellingly in the tunica adventitia. This review overviews the spectrum of resident stem/progenitor cells that have been documented in macro-and micro-vessels during developmental and adult life and considers the implications for a local, vascular wall stem cell niche(s) in the pathogenesis and treatment of cardiovascular and other diseases.

The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPI Flox ) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI Tie2 ) and myelomonocytic (TFPI LysM ) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI Tie2 (71% ؎ 0.9%, P < .001) and TFPI LysM (19% ؎ 0.6%, P < .001) compared with TFPI Flox littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI Tie2 mice but not TFPI LysM mice had increased ferric chlorideinduced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial-and myelomonocytic-derived TFPI. (Blood. 2010;116(10):1787-1794) IntroductionThe endothelium provides an antithrombotic interface with circulating blood which is generated in part by the coordinated expression of endothelial-derived anticoagulants. The regulated expression of these endothelial-derived proteins may account in part for differences in thrombotic phenotype among vessels. 1 Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor expressed in endothelial cells and regulates the initiation of coagulation by inhibiting tissue factor (TF)/factor VIIa activation of factor X.TFPI, originally known as lipoprotein associated coagulation inhibitor, was isolated from a hepatoma cell line. 2 TFPI circulates at low (nmol/L) levels in humans largely associated with lipoproteins. 3 Infusion of heparin increases circulating levels of TFPI in humans, and this increase has been attributed to displacement of TFPI from glycosoaminoglycans on the surface of endothelial cells. 4,5 As such, the endothelium has been thought to be the dominant source of circulating TFPI. However, TFPI is also expressed in platelets, vascular smooth muscle, cardiac myocytes, and monocyte/macrophages. 4,[6][7][8][9][10] The physiologic importance of TFPI is confirmed in that no known human deficiencies of TFPI have been reported. Homozygotic deletion of exon 4 in mice (which encodes the Kunitz 1 domain) resulted in embryonic lethality. 11 Heterozygotic deletion results in an increased response to acute and chronic vascular injury. [12][13][14] Conversely, vasculardirected overexpression of TFPI attenuates this response. 15 To better define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis, we generated mice with endothelial and monocytic-restricted deletion of exon 4, which encodes for the TFPI-K1 domain. We also used bone marrow transplantation as a means to generate ...

A paradox regarding the independent association of elevated BMI with reduced mortality after PCI is still evident in contemporary U.K. practice. This is seen in both stable and more acute clinical settings.