Abstract
Cardiovascular risk factors are associated with reduction in both the number and function of vascular progenitor cells. We hypothesized that 1) hypertension abrogates postnatal vasculogenesis, and 2) antihypertensive treatment based on the combination of perindopril (angiotensin-converting enzyme inhibitor) and indapamide (diuretic) may counteract hypertension-induced alteration in progenitor cell-related effects. Postischemic neovascularization was significantly lower in untreated spontaneously hypertensive rats (SHRs) compared with Wistar Kyoto (WKY) rats (p < 0.05). Treatment of SHRs with perindopril and the combination of perindopril/indapamide reduced the blood pressure levels and normalized vessel growth in ischemic area. Cotreatment with perindopril and indapamide increased vascular endothelial growth factor and endothelial nitric-oxide synthase protein contents, two key proangiogenic factors. It is interesting to note that 14 days after bone marrow mononuclear cell (BM-MNC) transplantation, revascularization was significantly lower in ischemic SHRs receiving BM-MNCs isolated from SHRs compared with those receiving BM-MNCs isolated from WKY rats (p < 0.05). Alteration in proangiogenic potential of SHR BM-MNCs was probably related to the reduction in their ability to differentiate into endothelial progenitor cells in vitro. Furthermore, the number of circulating endothelial progenitor cells (EPCs) was reduced by 3.1-fold in SHRs compared with WKY rats (p < 0.001). Treatments with perindopril or perindopril/indapamide restored the ability of BM-MNCs to differentiate in vitro into EPCs, increased the number of circulating EPCs, and re-established BM-MNC proangiogenic effects. Therefore, hypertension is associated with a decrease in the number of circulating progenitor cells and in the BM-MNC proangiogenic potential, probably leading to vascular complications in this setting. The combination of perindopril and indapamide counteracts hypertension-induced alterations in progenitor cell-related effects and restores blood vessel growth.
Footnotes
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J.-S.S. is supported by Agence Nationale de la Recherche (ANR) “Young Investigator” Grant JC05-45445 and Grants ANR-PCOD-05 028-01 and ANR-PCOD-05-022-02 “Cardiovascular, Obesity, and Diabetes.” Institut National de la Santé et de la Recherche Médicale U689 is a partner of the European Vascular Genomics Network, a Network of Excellence granted by the European Commission (Contract LSHM-CT-2003-503254). This study was also supported by grants from Naturalia and Biologia and Servier.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.131532.
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ABBREVIATIONS: VEGF, vascular endothelial growth factor; SHR, spontaneously hypertensive rat; EPC, endothelial progenitor cell; ACE, angiotensin-converting enzyme; WKY, Wistar Kyoto; PBS, phosphate-buffered saline; Ang II, angiotensin II; eNOS, endothelial nitric-oxide synthase; BM-MNC, bone marrow mononuclear cell; AcDil-LDL, 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine-labeled acetylated low-density lipoprotein.
- Received September 11, 2007.
- Accepted February 27, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Activate Postnatal Vasculogenesis in Spontaneously Hypertensive Rats
