Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved

<jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> Blood outgrowth endothelial cells ( <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s) mediate therapeutic neovascularization in experimental models, but outgrowth characteristics and functionality of <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s from patients with ischemic cardiomyopathy ( <jats:styled-content style="fixed-case">ICMP</jats:styled-content> ) are unknown. We compared outgrowth efficiency and in vitro and in vivo functionality of <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s derived from <jats:styled-content style="fixed-case">ICMP</jats:styled-content> with <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s from age‐matched ( <jats:styled-content style="fixed-case">ACON</jats:styled-content> ) and healthy young ( <jats:styled-content style="fixed-case">CON</jats:styled-content> ) controls. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> We isolated 3.6±0.6 <jats:styled-content style="fixed-case">BOEC</jats:styled-content> colonies/100×10 <jats:sup>6</jats:sup> mononuclear cells ( <jats:styled-content style="fixed-case">MNC</jats:styled-content> s) from 60‐mL blood samples of <jats:styled-content style="fixed-case">ICMP</jats:styled-content> patients (n=45; age: 66±1 years; <jats:styled-content style="fixed-case">LVEF</jats:styled-content> : 31±2%) versus 3.5±0.9 colonies/100×10 <jats:sup>6</jats:sup> <jats:styled-content style="fixed-case">MNC</jats:styled-content> s in <jats:styled-content style="fixed-case">ACON</jats:styled-content> (n=32; age: 60±1 years) and 2.6±0.4 colonies/100×10 <jats:sup>6</jats:sup> <jats:styled-content style="fixed-case">MNC</jats:styled-content> s in <jats:styled-content style="fixed-case">CON</jats:styled-content> (n=55; age: 34±1 years), <jats:italic>P</jats:italic> =0.29. Endothelial lineage ( <jats:styled-content style="fixed-case">VEGFR</jats:styled-content> 2 <jats:sup>+</jats:sup> / <jats:styled-content style="fixed-case">CD</jats:styled-content> 31 <jats:sup>+</jats:sup> / <jats:styled-content style="fixed-case">CD</jats:styled-content> 146 <jats:sup>+</jats:sup> ) and progenitor ( <jats:styled-content style="fixed-case">CD</jats:styled-content> 34 <jats:sup>+</jats:sup> / <jats:styled-content style="fixed-case">CD</jats:styled-content> 133 <jats:sup>−</jats:sup> ) marker expression was comparable in <jats:styled-content style="fixed-case">ICMP</jats:styled-content> and <jats:styled-content style="fixed-case">CON</jats:styled-content> . Growth kinetics were similar between groups ( <jats:italic>P</jats:italic> =0.38) and not affected by left ventricular systolic dysfunction, maladaptive remodeling, or presence of cardiovascular risk factors in <jats:styled-content style="fixed-case">ICMP</jats:styled-content> patients. In vitro neovascularization potential, assessed by network remodeling on Matrigel and three‐dimensional spheroid sprouting, did not differ in <jats:styled-content style="fixed-case">ICMP</jats:styled-content> from (A) <jats:styled-content style="fixed-case">CON</jats:styled-content> . Secretome analysis showed a marked proangiogenic profile, with highest release of angiopoietin‐2 (1.4±0.3×10 <jats:sup>5</jats:sup>  pg/10 <jats:sup>6</jats:sup> <jats:styled-content style="fixed-case">ICMP</jats:styled-content> ‐ <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s) and placental growth factor (5.8±1.5×10 <jats:sup>3</jats:sup>  pg/10 <jats:sup>6</jats:sup> <jats:styled-content style="fixed-case">ICMP BOEC</jats:styled-content> s), independent of age or ischemic disease. Senescence‐associated β‐galactosidase staining showed comparable senescence in <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s from <jats:styled-content style="fixed-case">ICMP</jats:styled-content> (5.8±2.1%; n=17), <jats:styled-content style="fixed-case">ACON</jats:styled-content> (3.9±1.1%; n=7), and <jats:styled-content style="fixed-case">CON</jats:styled-content> (9.0±2.8%; n=13), <jats:italic>P</jats:italic> =0.19. High‐resolution microcomputed tomography analysis in the ischemic hindlimb of nude mice confirmed increased arteriogenesis in the thigh region after intramuscular injections of <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s from <jats:styled-content style="fixed-case">ICMP</jats:styled-content> ( <jats:italic>P</jats:italic> =0.025; n=8) and <jats:styled-content style="fixed-case">CON</jats:styled-content> ( <jats:italic>P</jats:italic> =0.048; n=5) over vehicle control (n=8), both to a similar extent ( <jats:italic>P=</jats:italic> 0.831). </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s can be successfully culture‐expanded from patients with <jats:styled-content style="fixed-case">ICMP</jats:styled-content> . In contrast to impaired functionality of <jats:styled-content style="fixed-case">ICMP</jats:styled-content> ‐derived bone marrow <jats:styled-content style="fixed-case">MNC</jats:styled-content> s, <jats:styled-content style="fixed-case">BOEC</jats:styled-content> s retain a robust proangiogenic profile, both in vitro and in vivo, with therapeutic potential for targeting ischemic disease. </jats:p> </jats:sec>