Cyp2c44gene Disruption is Associated with Increased Hematopoietic Stem Cells: Implication in Chronic Hypoxia-Induced Pulmonary Hypertension

We have recently demonstrated that disruption of the murine cytochrome P450 2c44gene (Cyp2c44)exacerbates chronic hypoxia-induced pulmonary artery remodeling and hypertension in mice. Subsequently, we serendipitously found that Cyp2c44gene disruption also increases hematopoietic stem cell (HSC) number in bone marrow and blood. Therefore, the objective of this study was to investigate whether CYP2C44-derived eicosanoids regulate HSC proliferation/cell growth and whether increased HSCs contribute to chronic hypoxia-induced remodeling of pulmonary arteries in Cyp2c44knockout mice. Our findings demonstrated that lack of the CYP2C44 epoxygenase, which catalyzed the oxidation of arachidonic acid to epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic (HETE) acids, increases the numbers of: 1] HSC (CD34⁺, CD117⁺, and CD133⁺); 2] proangiogenic (CD34⁺CD133⁺, CD34⁺CD117⁺CD133⁺) cells; and 3] immunogenic/inflammatory (CD34⁺CD11b⁺, CD133⁺CD11b⁺, F4/80⁺, CD11b⁺, and F4/80⁺CD11b⁺) macrophages, in bone marrow and blood as compared to wild-type mice. Among the various CYP2C44-derived arachidonic acid, only 15-HETE decreased CD117⁺cell numbers, when applied to bone marrow cell cultures. Interestingly, CD133⁺and Von Willebrand factor positive cells, which are derived from pro-angiogenic stem cells, are increased in bone marrow and blood and lungs of mice exposed to chronic hypoxia, and in remodeled and occluded pulmonary arteries of CYP2C44-deficient mice. In conclusion, our results demonstrated that CYP2C44-derived 15-HETE played a critical role in down regulating HSC proliferation and growth, because disruption of Cyp2c44gene increased HSCs that potentially contributed to chronic hypoxia-induced pulmonary arterial remodeling and occlusion.