Endothelial progenitor cells dysfunction and senescence: contribution to oxidative stress

Abstract

The identification of endothelial progenitor cells (EPCs) has led to a significant paradigm in the field of vascular biology and opened a door to the development of new therapeutic approaches. Based on the current evidence, it appears that EPCs may make both direct contribution to neovascularization and indirectly promote the angiogenic function of local endothelial cells via secretion of angiogenic factors. This concept of arterial wall repair mediated by bone marrow (BM)-derived EPCs provided an alternative to the local "response to injury hypothesis" for development of atherosclerotic inflammation. Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability. EPCs function may also be highly dependent on a well-controlled oxidant stress because EPCs NO bioavailability (which is highly sensitive to oxidant stress) is critical for their in vivo function. The critical question is whether oxidant damage directly leads to an impairment in EPCs function. It was revealed that activation of angiotensin II (Ang II) type 1 receptor stimulates nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase in the vascular endothelium and leads to production of reactive oxygen species. We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction. Consistently, both Ang II receptor 1 blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors have been reported to increase the number of EPCs in patients with cardiovascular disease. In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.

Keywords: Endothelial progenitor cell; angiotensin II; nitric oxide.; oxidative stress; senescence; telomerase.

Fig. (1). Mobilization, recruitment, and differentiation of human, bone marrow-derived angiogenic progenitor cells.

Hemangioblast, originated from hematopoietic cell, is resident in bone marrow niches, in a quiescent state. The stimulation by circulating cytokines induces the activation of matrix metalloproteinase-9 (MMP-9) through an Akt, nitric oxide dependent pathway. MMP-9 promotes the transformation of membrane bound Kit-ligand to a soluble Kit-ligand. This activation is followed by detachment of early c-Kit+ progenitor cells from the bone marrow stromal niche and their subsequent movement to the vascular zone of the bone marrow. An important regulation is VEGF and SDF-1, which binds to its receptor VEGFR-2 and CXCR4, respectively, thus mediating further maturation of the cascade hemangioblast-angioblast-early endothelial progenitor cells (EPC)-late EPCs. Bone marrow-derived EPCs are of hematopoietic origin and possibly derive from the hemangioblast. These early progenitors (CD133⁺/CD34⁺/VEGFR-2⁺/CD14^-) represent a small population with proliferative potential, capable to give rise to late endothelial outgrowth. Cells of myeloid origin (CD14+) may also trans-differentiate into endothelial cells and secret angiogenic factors, but their proliferative potential is limited and they did not generate a stable late outgrowth.

Fig. (2). Oxidative stresses on endothelial progenitor cells (EPCs) in cardiovascular diseases.

EPCs repair cardiovascular damage. Oxidative stress caused by dyslipidemia, diabetes mellitus, or hypertension interferes with the ability of EPCs proliferation, differentiation, and mobilization in bone marrow. Oxidative stress also induces EPCs senescence. These negative effects of oxidative stress on EPCs number and function bring the equilibrium between cellular repair and injury out of balance, resulting in the progression of cardiovascular damages.

Fig. (3). Potential mechanisms of Ang II-induced EPCs senescence.

Ang II stimulates gp91^phox expression, a subunit of NADPH oxidase, via the angiotensin type 1 (AT₁) receptor, which leads to the increase in superoxide (O₂^-). Furthermore, peroxynitrite is formed form the inteaction of O₂^- with nitric oxide (NO). Both superoxide and peroxynitrite inactivate telomerase activity, which induces the impairment of telomere structure integrity, resulting in senescence.