Abstract-The role of prostaglandin production in the control of regenerative function of endothelial progenitor cells (EPCs) has not been studied. We hypothesized that activation of cyclooxygenase (COX) enzymatic activity and the subsequent production of prostacyclin (PGI 2 ) is an important mechanism responsible for the regenerative function of EPCs. In the present study, we detected high levels of COX-1 protein expression and PGI 2 biosynthesis in human EPCs outgrown from blood mononuclear cells. Expression of COX-2 protein was almost undetectable under basal conditions but significantly elevated after treatment with tumor necrosis factor-␣. Condition medium derived from EPCs hyperpolarized human coronary artery smooth muscle cells, similar to the effect of the PGI 2 analog iloprost. The proliferation and in vitro tube formation by EPCs were inhibited by the COX inhibitor indomethacin or by genetic inactivation of COX-1 or PGI 2 synthase with small interfering (si)RNA. Impaired tube formation and cell proliferation induced by inactivation of COX-1 were rescued by the treatment with iloprost or the selective peroxisome proliferator-activated receptor (PPAR)␦ agonist GW501516 but not by the selective PGI 2 receptor agonist cicaprost. [1][2][3][4][5][6][7][8][9][10][11] However, the mechanisms underlying the reported therapeutic effects of EPCs are poorly understood, thus limiting successful translation of EPC-based therapies into the clinical arena. Arachidonic acid metabolism via cyclooxygenase (COX)-1 and/or COX-2 in mature endothelium is of major importance in cardiovascular homeostasis. 12,13 Prostacyclin (PGI 2 ) is a key vasoactive substance released from the endothelium after activation of COX(s) by chemical or physical stimuli. 12,13 Most importantly, PGI 2 is known to have a wide range of vasoprotective and therapeutic effects. 14 Recently, it has been recognized that PGI 2 also has stimulatory effects on angiogenesis. [15][16][17][18][19] Despite the fact that a substantial amount of literature is available on functional and therapeutic significance of COX(s) and PGI 2 in the vasculature, the role of arachidonic acid metabolism in the regenerative function of EPCs has not been examined. In the present study, we hypothesized that activation of COX isoforms and high production of PGI 2 are important mechanisms responsible for the regenerative function of EPCs. We provide compelling evidence that the proangiogenic effects of human EPCs are in part dependent on the biosynthesis and release of PGI 2 , and subsequent activation of peroxisome proliferatoractivated receptor (PPAR)␦.

Sepsis, the systemic inflammatory response to infection, imposes a high demand for bodily adaptation, with the cardiovascular response a key determinant of outcome. The homeostatic elements that secure cardiac tolerance in the setting of the sepsis syndrome are poorly understood. Here, in a model of acute septic shock induced by endotoxin challenge with Escherichia coli lipopolysaccharide (LPS), knockout of the KCNJ8 gene encoding the vascular Kir6.1 K(ATP) channel pore predisposed to an early and profound survival disadvantage. The exaggerated susceptibility provoked by disruption of this stress-responsive sensor of cellular metabolism was linked to progressive deterioration in cardiac activity, ischemic myocardial damage, and contractile dysfunction. Deletion of KCNJ8 blunted the responsiveness of coronary vessels to cytokine- or metabolic-mediated vasodilation necessary to support myocardial perfusion in the wild-type (WT), creating a deficit in adaptive response in the Kir6.1 knockout. Application of a K(ATP) channel opener drug improved survival in the endotoxic WT but had no effect in the Kir6.1 knockout. Restoration of the dilatory capacity of coronary vessels was required to rescue the Kir6.1 knockout phenotype and reverse survival disadvantage in lethal endotoxemia. Thus, the Kir6.1-containing K(ATP) channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.

The authors demonstrated that autologous transplantation of EPCs preserves pulmonary endothelial function and maintains the integrity of pulmonary alveolar-capillary barrier. Transplantation of EPCs can be a novel cell-based, endothelium-targeted therapeutic strategy for prevention and treatment of ALI/ARDS.

High-dose morphine impaired angiogenesis, increased systemic oxidative stress, and impaired mobilization of endothelial progenitor cells. This study emphasizes the potential detrimental effect of high-dose morphine on angiogenesis after systemic administration.

Objective-One potential mechanism through which obesity exerts adverse effects on the vascular system is by increasing aortic stiffness, a change known to be predictive of increased cardiovascular mortality. The aim of this study was to investigate the pathophysiology that links obesity to aortic stiffening. Approach and Results-Obese (ob/ob) mice were used to examine physical, morphological, and molecular changes in the aorta in response to obesity. ob/ob mice had increased aortic pulse wave velocity and tissue rigidity. ob/ob aorta exhibited decreases of lysyl oxidase (LOX) activity and cross-linked elastin, and increases of elastin fragmentation and elastolytic activity. The aortas of ob/ob mice were surrounded by a significant amount of proinflammatory and pro-oxidative perivascular adipose tissue. In vitro studies revealed that the conditioned medium from differentiated adipocytes or the perivascular adipose tissue of ob/ob mice attenuated LOX activity. Furthermore, inhibition of LOX in wild-type lean mice caused elastin fragmentation and induced a significant increase in pulse wave velocity. Finally, we found that obese humans had stiffer arteries and lower serum LOX levels than do normal-weight humans. Conclusion-Our results demonstrated that obesity resulted in aortic stiffening in both humans and mice, and established a causal relationship between LOX downregulation and aortic stiffening in obesity.