Local Oxidative and Nitrosative Stress Increases in the Microcirculation during Leukocytes-Endothelial Cell Interactions

Leukocyte-endothelial cell interactions and leukocyte activation are important factors for vascular diseases including nephropathy, retinopathy and angiopathy. In addition, endothelial cell dysfunction is reported in vascular disease condition. Endothelial dysfunction is characterized by increased superoxide (O2•−) production from endothelium and reduction in NO bioavailability. Experimental studies have suggested a possible role for leukocyte-endothelial cell interaction in the vessel NO and peroxynitrite levels and their role in vascular disorders in the arterial side of microcirculation. However, anti-adhesion therapies for preventing leukocyte-endothelial cell interaction related vascular disorders showed limited success. The endothelial dysfunction related changes in vessel NO and peroxynitrite levels, leukocyte-endothelial cell interaction and leukocyte activation are not completely understood in vascular disorders. The objective of this study was to investigate the role of endothelial dysfunction extent, leukocyte-endothelial interaction, leukocyte activation and superoxide dismutase therapy on the transport and interactions of NO, O2•− and peroxynitrite in the microcirculation. We developed a biotransport model of NO, O2•− and peroxynitrite in the arteriolar microcirculation and incorporated leukocytes-endothelial cell interactions. The concentration profiles of NO, O2•− and peroxynitrite within blood vessel and leukocytes are presented at multiple levels of endothelial oxidative stress with leukocyte activation and increased superoxide dismutase accounted for in certain cases. The results showed that the maximum concentrations of NO decreased ∼0.6 fold, O2•− increased ∼27 fold and peroxynitrite increased ∼30 fold in the endothelial and smooth muscle region in severe oxidative stress condition as compared to that of normal physiologic conditions. The results show that the onset of endothelial oxidative stress can cause an increase in O2•− and peroxynitrite concentration in the lumen. The increased O2•− and peroxynitrite can cause leukocytes priming through peroxynitrite and leukocytes activation through secondary stimuli of O2•− in bloodstream without endothelial interaction. This finding supports that leukocyte rolling/adhesion and activation are independent events

Radial concentration profiles at locations P₁ and P₂ for the Case 1.

<p><b>Panel A</b> and <b>B</b> shows the radial concentration profiles of NO, O₂^•− and peroxynitrite at the location P₁ and P₂, respectively.</p

Endothelial, capillary and leukocyte based NO and O₂^•− production rates and SOD concentration for the different cases simulated.

1<p><b>P_i,L</b> refers to the production rate of NO and O₂^•− from the leukocytes L1, L2 and L3.</p

Concentration range of NO, O₂^•− and peroxynitrite at different regions of the arteriole geometry.

<p>Concentration range of NO, O₂^•− and peroxynitrite at different regions of the arteriole geometry.</p

Concentration distribution under endothelial oxidative stress, activated leukocytes and increased SOD concentration (Case 4).

<p>The NO, O₂^•− and peroxynitrite concentration distribution are shown for the entire arteriolar geometry in <b>Panels A, C, and E,</b> respectively and across the 200–300 µm region in <b>Panels B, D and F,</b> respectively. The O₂^•− production in the endothelium and capillary in this case were 20% of their respective NO production and the leukocytes were in activated state producing NO and O₂^•−. The SOD concentration across all the regions of the arteriole and within the leukocytes was set at 10 µM.</p

Concentration distribution under combination of endothelial oxidative stress and activation of leukocytes (Case 3).

<p>The NO, O₂^•− and peroxynitrite concentration distribution are shown for the entire arteriolar geometry in <b>Panels A, C, and E,</b> respectively and across the 200–300 µm region in <b>Panels B, D and F,</b> respectively. The O₂^•− production in the endothelium and capillary in this case were 20% of their respective NO production and the leukocytes were in activated state producing NO and O₂^•−.</p

Radial concentration profiles at locations P₁ and P₂ for the Case 4.

<p><b>Panel A</b> and <b>B</b> shows the radial concentration profiles of NO, O₂^•− and peroxynitrite at the location P₁ and P₂, respectively.</p

Radial concentration profiles at locations P₁ and P₂ for the Case 5.

<p><b>Panel A </b><b>and </b><b>B</b> shows the radial concentration profiles of NO, O₂^•− and peroxynitrite at the location P₁ and P₂, respectively.</p

Geometrical description of the problem.

<p><b>Panel A</b> shows the schematic of the arteriolar geometry. The geometry consists of concentric cylinders representing the different regions of the arteriole. The different regions fall under the category of either luminal or abluminal region. The luminal and abluminal regions are separated by the endothelial region (E). The luminal region consists of the RBC rich core (CR) and RBC free plasma region (CF). The abluminal region consists of the interstitial region (IS), smooth muscle region (SM), non-perfused (NPT) and capillary perfused (PT) parenchymal regions. L1, L2 and L3 represent the leukocytes interacting with the endothelium. P_in and P_out represent the inlet and outlet of the arteriolar/vessel segment, respectively. P₁ and P₂ represent the locations where the radial concentration profiles of NO, O₂^•− and peroxynitrite were obtained and are located at distances of 230 and 345 µm, respectively from P_in. <b>Panel B</b> shows the schematic of finite element mesh grid with relative accuracy set to 0.001.</p