Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively.Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling.These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries

The role of angiotensin II in regulating vascular structural and functional changes in hypertension

A major hemodynamic abnormality in hypertension is increased peripheral resistance due to changes in vascular structure and function. Structural changes include reduced lumen diameter and arterial wall thickening. Functional changes include increased vasoconstriction and/or decreased vasodilation. These processes are influenced by many humoral factors, of which angiotensin II (Ang II) seems to be critical. At the cellular level, Ang II stimulates vascular smooth muscle cell growth, increases collagen deposition, induces inflammation, increases contractility, and decreases dilation. Molecular mechanisms associated with these changes in hypertension include upregulation of many signaling pathways, including tyrosine kinases, mitogen-activated protein kinases, RhoA/Rho kinase, and increased generation of reactive oxygen species. This review focuses on the role of Ang II in vascular functional and structural changes of small arteries in hypertension. In addition, cellular processes whereby Ang II influences vessels in hypertension are discussed. Finally, novel concepts related to signaling pathways by which Ang II regulates vascular smooth muscle cells in hypertension are introduced

Hypertensive vasculopathy

Essential hypertension is characterized by an increase in total peripheral vascular resistance, due primarily to a decrease in lumen diameter and an increase in media thickness. Underlying these phenomena are altered vascular tone (decreased relaxation and/or increased contraction) and structural remodeling. Endothelial dysfunction and arterial remodeling characterize the vascular phenotype of hypertension, known as “hypertensive vasculopathy.” Initial factors contributing to vasculopathy of hypertension involve increased transmural pressure, changes in blood flow, impaired endothelial function, and altered vascular smooth muscle cell (VSMC) contractility. More chronic changes are associated with perturbed VSMC growth, migration, differentiation, calcification and inflammation, and production of extracellular matrix proteins, responsible for structural remodeling. At the level of the vascular cells, receptors are activated by vasoactive agents and mechanical forces triggering intracellular signaling pathways and generation of reactive oxygen species (ROS). These subcellular events underlie VSMC dedifferentiation, realignment, calcification, and growth and stimulate inflammation, fibrosis, and osteogenic transformation, which contribute to endothelial dysfunction and thickening of the vascular wall. Such changes play a major role in the vasculopathy of hypertension