title: Analysis of CD45- [CD34+/KDR+] endothelial progenitor cells as juvenile protective factors in a rat model of ischemic-hemorrhagic stroke.
abstract: BACKGROUND
  Identification of juvenile protective factors (JPFs) which are altered with age and contribute to adult-onset diseases could identify novel pathways for reversing the effects of age, an accepted non-modifiable risk factor to adult-onset diseases. Since endothelial progenitor cells (EPCs) have been observed to be altered in stroke, hypertension and hypercholesterolemia, said EPCs are candidate JPFs for adult-onset stroke. A priori, if EPC aging plays a 'master-switch JPF-role' in stroke pathogenesis, juvenile EPC therapy alone should delay stroke-onset. Using a hypertensive, transgenic-hyperlipidemic rat model of spontaneous ischemic-hemorrhagic stroke, spTg25, we tested the hypothesis that freshly isolated juvenile EPCs are JPFs that can attenuate stroke progression and delay stroke onset.
  
  
  RESULTS
  FACS analysis revealed that CD45- [CD34+/KDR+] EPCs decrease with progression to stroke in spTg25 rats, exhibit differential expression of the dual endodthelin-1/VEGFsp receptor (DEspR) and undergo differential DEspR-subtype specific changes in number and in vitro angiogenic tube-incorporation. In vivo EPC infusion of male, juvenile non-expanded cd45-[CD34+/KDR+] EPCs into female stroke-prone rats prior to stroke attenuated progression and delayed stroke onset (P<0.003). Detection of Y-chromosome DNA in brain microvessels of EPC-treated female spTg25 rats indicates integration of male EPCs into female rat brain microvessels. Gradient-echo MRI showed delay of ischemic-hemorrhagic lesions in EPC-treated rats. Real-time RT-PCR pathway-specific array-analysis revealed age-associated gene expression changes in CD45-[CD34+/KDR]EPC subtypes, which were accelerated in stroke-prone rats. Pro-angiogenic genes implicated in intimal hyperplasia were increased in stroke-prone rat EPCs (P<0.0001), suggesting a maladaptive endothelial repair system which acts like a double-edged sword repairing while predisposing to age-associated intimal hyperplasia.
  
  
  CONCLUSIONS
  Altogether, the data demonstrate that CD45-[CD34/KDR+]EPCs are juvenile protective factors for ischemic hemorrhagic stroke as modeled in the spTg25-rat model. The ability to delay stroke onset emphasizes the importance of EPC-mediated roles in vascular health for ischemic-hemorrhagic stroke, a high unmet need.
authors: Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Julius L
authors: JL
authors: Decano
authors: Ann Marie
authors: AM
authors: Moran
authors: Nicholas
authors: N
authors: Giordano
authors: Nelson
authors: N
authors: Ruiz-Opazo
authors: Victoria L M
authors: VL
authors: Herrera
mesh_terms: D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D018952:Antigens, CD34 / Q000378:metabolism; D002545:Brain Ischemia / Q000517:prevention & control*; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D020011:Protective Agents / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism*; D020521:Stroke / Q000517:prevention & control*
chemical_list: D018952:Antigens, CD34; D020011:Protective Agents; D017493:Leukocyte Common Antigens
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