VENULAR CONTROL OF CAPILLARY PERFUSION IN THE PRESENCE OF CARDIOVASCULAR RISK FACTORS
Open Access
- Author:
- Nellore, Kavitha
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 23, 2004
- Committee Members:
- Norman R Harris, Committee Chair/Co-Chair
Peter J Butler, Committee Member
David A Antonetti, Committee Member
Herbert Herling Lipowsky, Committee Member - Keywords:
- Nitric Oxide
Diabetes
Hypercholesterolemia
Microcirculation
Arterio-Venular Communication
Capillary flow - Abstract:
- The purpose of this study was to investigate and counteract dysfunctional control of capillary flow in hypercholesterolemia and diabetes. Capillary flow is controlled by arteriolar tone, which in turn is influenced by mediators released from closely paired venules in a mechanism that involves nitric oxide (NO). However, venular control of capillary flow is altered with the cardiovascular risk factors hypercholesterolemia and diabetes. In our experiments involving the microcirculation of the rat mesentery, the arteriolar pathway leading to the capillary was videotaped to measure the percent of the surrounding area (within 15 microns) that was occupied by a venule (% pairing). Capillary velocity was measured using an optical Doppler velocimeter. A positive correlation between capillary velocity and % pairing observed in normal rats was not observed during NO synthase inhibition, or in either hypercholesterolemic or diabetic rats. However, positive correlations between the two parameters were found in hypercholesterolemia when the rats were given drinking water supplementation of L-arginine or an injection of anti-neutrophil serum. In diabetic rats, venular control of capillary perfusion was restored by treatment with fucoidan, which inhibits venular leukocyte adhesion. These results indicate that dysfunctional venular control of capillary perfusion in both hypercholesterolemia and diabetes may be a consequence of a neutrophil-mediated deficiency of NO. We also found that % pairing levels in diabetic rats decreased approximately 50% in comparison to normal rats, which might also contribute to inadequate control of capillary perfusion in diabetes. In our method of calculating the parameter % pairing, we assumed that 15 microns gives an adequate measure of the extent of arterio-venular communication capability. This distance might not be appropriate for all mediators and situations. Also, the current method of calculation is not based on a diffusion equation, although we assume that communication between the arteriole and venule will involve diffusion of some mediator. In order to address these concerns, we developed an additional pairing parameter, based on a mathematical model of diffusion between a venule and an arteriole, solved by finite element analysis. Comparisons show that the results of our study are similar whether using the diffusional pairing parameter or the % pairing based on area. Arteriolar tone is partially controlled by diffusing mediators released by closely paired venules, and is reported to depend on venular shear and venular leukocyte adherence. Arteriolar and venular wall concentrations of NO were measured in control and diabetic rat mesentery with fluorescent diaminofluorescein-2-diacetate (DAF-2-DA); tissue NO was measured with DAF-2. Microvascular NO in diabetic rats was found to be significantly lower (< 50%) than in controls. In normal rats, arteriolar NO demonstrated a positive correlation with venular NO and measurements of venular shear, and a negative correlation with measurements of venular leukocyte adherence. Diabetes eliminated all these correlations. No correlation was present between arteriolar NO and arteriolar shear in either normal or diabetic rats. These results indicate that arteriolar NO is enhanced by venular shear in normal but not in diabetic rats and this might contribute to dysfunctional venular control of capillary perfusion in diabetes.