Vascular Disease: A New Progenitor Biology

Abstract

Vascular disease is primarily the result of atherosclerosis which affects all layers of the adult vessel wall. Our understanding of atherosclerosis has evolved over the past three decades; from initial hypotheses based on lipid deposition and fibrocellular proliferation within the intima of the vessel wall to a more complex interplay between conventional risk factors, inflammation and the immune system implicating pan-vascular biologic processes. More recently circulating progenitor cells have been shown to possess diverse differentiation capacity within the remodelling vessel wall. Current investigation of atherosclerosis therefore encompasses an expanding field of biological science; from molecular genetics, classical vascular biology, and immunology to stem cell biology and vasculogenesis. However, a decade after their initial description, scientists still know little about the proximate relationship between vascular progenitor cells and atherosclerosis progression or stability. In recent years, the discovery of progenitor cells of myeloid origin has offered the exciting prospect of merging classical concepts of myeloid cell biology in atherosclerosis with evolving concepts of myeloid cell plasticity and endothelial / smooth muscle cells differentiation within the injured vessel wall. In this context, early stage atherosclerosis associated with vascular injury may involve neovascularisation and re-endothelialisation in which a significant contribution comes from bone marrow-derived vascular progenitor cells. For this review, emphasis will be on endothelial progenitor cells (EPC), smooth muscle progenitor cells (SPC) and putative myeloid precursors.

Endothelial Differentiation of Hematopoietic Stem and Progenitor Cells from Patients with Multiple Myeloma

“…Furthermore, HSPCs generated a capillary-like network similarly to MMECs. Overall, these data show for the first time that, in MM patients, circulating HSPCs are driven by VEGF, FGF-2, and IGF to become mature endothelial cells through a vasculogenic pathway, much in the same way as normal bone marrow and circulating and cord blood HSPCs (26,27). In bone marrow biopsies of patients with MM, but not MGUS, we observed some CD133 + HSPCs in the constitution of the vessel wall of newly forming blood vessels together with FVIII-RA + , VEGFR-2 + , and VE-cadherin + MMECs.…”

“…Compared with the latter, these HSPCs lacked the VE-cadherin expression. When exposed to VEGF, FGF-2, and IGF, these HSPCs differentiated into mature endothelial cells because they progressively lost CD133 and acquired the expression of FVIII-RA, VEGFR-2, and VE-cadherin, which are typical markers of mature endothelial cells (19,26,27). VEGFR-1 was acquired too and probably mediates HSPC recruitment and migration (28).…”

Clinical Potential of Adult Vascular Progenitor Cells

“…A leukocyte population coexpressing dendritic cell and endothelial cell markers was found to infiltrate tumor and assemble neovasculature. 33 Monocyte (CD34 ϩ /CD14 ϩ )-derived EPCs can also express a range of proangiogenic factors, such as hepatocyte growth factor, vascular endothelial growth factor, and granulocyte colonystimulating factor, providing one mechanism whereby these cells may contribute to neoangiogenesis 33 or in-stent restenosis 33 when implanted in vivo. Of concern is the increased incidence of in-stent restenosis, 28 although this adverse effect was not observed in most studies.…”

“…10,28,29 Significant contributions of bone marrow-derived myeloid lineage cells toward neovascularization and reendothelialization have also been reported in transplant atherosclerosis associated with vascular injury. 33 These cells may thus represent a double-edged sword in terms of therapeutic versus pathological angiogenesis.…”

Endothelial Progenitor Cell Number: A Convergence of Cardiovascular Risk Factors

“…The modern concept that circulating marrow cells, EPCs, circulate in adult animals and repair the vasculature originates stems from the observation in the late 90s that marrowderived mononuclear cells circulate in adult animals and directly contribute to neovascularization in animal models of hindlimb ischemia, myocardial infarct remodeling and post-stroke neovascularization (Asahara, Murohara et al 1997;Asahara, Masuda et al 1999;Zhang, Zhang et al 2002;Metharom and Caplice 2007). The clinical relevance of EPC numbers was brought to the forefront cardiovascular risk prognostication when EPC numbers were shown to correlate positively with flow mediated brachial artery reactivity (a measure of endothelial function) and inversely with the Framingham risk score (Hill, Zalos et al 2003;Ghani, Shuaib et al 2005;Chironi, Walch et al 2007).…”