Effects of a Global Null Mutation on Murine PVAT and Cardiovascular Function

Ashley Soucy, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Christian Potts, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Abigail Kaija, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Anne Harrington, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Marissa McGilvrey, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
George L. Sutphin, The Jackson Laboratory, Bar Harbor, ME (G.L.S., R.K.).
Ron Korstanje, Graduate School of Biomedical Science and Engineering, University of Maine, Orono (A.S., M.M.G., R.K., I.P., C.V., L.L.).
Benjamin Tero, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Jacob Seeker, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Ilka Pinz, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Calvin Vary, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Larisa Ryzhova, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Lucy Liaw, MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).

Abstract

BACKGROUND: RAB27A, a modulator of secretion, is expressed within vessels and perivascular adipose tissue. We hypothesized that loss of RAB27A would alter cardiovascular function. METHODS: Body weight of mice was measured from 2 to 18 months of age, along with glucose resorption at 6 and 12 months of age and glucose sensitivity at 18 months of age. Body weight and cellular and molecular features of perivascular adipose tissue and aortic tissue were examined in a novel C57BL/6J null strain. Analyses included morphometric quantification and proteomic analyses. Wire myography measured vasoreactivity, and echocardiography measured cardiac function. Comparisons across ages and genotypes were evaluated via 2-way ANOVA with multiple comparison testing. Significance for myography was determined via 4-parameter nonlinear regression testing. RESULTS: Genome-wide association data linked rare human variants with body mass index and glucose handling. Changes in glucose tolerance were observed in male mice at 18 months of age. In WT (wild-type) and null male mice, body weight, adipocyte lipid area, and aortic area increased with age. In female mice, only body weight increased with age, independent of RAB27A presence. Protein signatures from male null mice suggested greater associations with cardiovascular and metabolic phenotypes compared with female tissues. Wire myography results showed null males exhibited increased vasoconstriction and reduced vasodilation at 8 weeks of age. null females exhibited increased vasoconstriction and vasodilation at 20 weeks of age. Consistent with these vascular changes, male null mice experienced age-related cardiomyopathy, with severe differences observed by 21 weeks of age. CONCLUSIONS: Global RAB27A loss impacted perivascular adipose tissue and thoracic aorta proteomic signatures, altered vasocontractile responses, and decreased left ventricular ejection fraction in mice.