The Role of Reactive Oxygen Species in Microvascular Remodeling

The microcirculation is a portion of the vascular circulatory system that consists of resistance arteries, arterioles, capillaries and venules. It is the place where gases and nutrients are exchanged between blood and tissues. In addition the microcirculation is the major contributor to blood flow resistance and consequently to regulation of blood pressure. Therefore, structural remodeling of this section of the vascular tree has profound implications on cardiovascular pathophysiology. This review is focused on the role that reactive oxygen species (ROS) play on changing the structural characteristics of vessels within the microcirculation. Particular attention is given to the resistance arteries and the functional pathways that are affected by ROS in these vessels and subsequently induce vascular remodeling. The primary sources of ROS in the microcirculation are identified and the effects of ROS on other microcirculatory remodeling phenomena such as rarefaction and collateralization are briefly reviewed

Data from: Mechanical factors direct mouse aortic remodeling during early maturation

Numerous diseases have been linked to genetic mutations that lead to reduced amounts or disorganization of arterial elastic fibres. Previous work has shown that mice with reduced amounts of elastin (Eln+/−) are able to live a normal lifespan through cardiovascular adaptations, including changes in haemodynamic stresses, arterial geometry and arterial wall mechanics. It is not known if the timeline and presence of these adaptations are consistent in other mouse models of elastic fibre disease, such as those caused by the absence of fibulin-5 expression (Fbln5−/−). Adult Fbln5−/− mice have disorganized elastic fibres, decreased arterial compliance and high blood pressure. We examined mechanical behaviour of the aorta in Fbln5−/− mice through early maturation when the elastic fibres are being assembled. We found that the physiologic circumferential stretch, stress and modulus of Fbln5−/− aorta are maintained near wild-type levels. Constitutive modelling suggests that elastin contributions to the total stress are decreased, whereas collagen contributions are increased. Understanding how collagen fibre structure and mechanics compensate for defective elastic fibres to meet the mechanical requirements of the maturing aorta may help to better understand arterial remodelling in human elastinopathies

Data for fitting constitutive model

Pressure, diameter, force, and axial stretch data combined for six loading protocols and used to fit the constitutive model in the manuscript. Unloaded dimensions for each aorta are also included

Lysophosphatidic acid induces integrin activation in vascular smooth muscle and alters arteriolar myogenic vasoconstriction

In vascular smooth muscle cells (VSMC) increased integrin adhesion to extracellular matrix (ECM) proteins, as well as the production of reactive oxygen species (ROS) are strongly stimulated by lysophosphatidic acid (LPA). We hypothesized that LPA-induced generation of ROS increases integrin adhesion to the ECM. Using atomic force microscopy (AFM) we determined the effects of LPA on integrin adhesion to fibronectin (FN) in VSMC isolated from rat (Sprague–Dawley) skeletal muscle arterioles. In VSMC, exposure to LPA (2µM) doubled integrin-FN adhesion compared to control cells (P<0.05). LPA-induced integrin-FN adhesion was reduced by pre-incubation with antibodies against β1 and β3 integrins (50µg/ml) by 66% (P<0.05). Inhibition of LPA signaling via blockade of the LPA G-protein coupled receptors LPAR1 and LPAR3 with Ki16425 (10µM) reduced the LPA-enhanced adhesion of VSCM to FN by 40% (P<0.05). Suppression of ROS with tempol (250µM) or apocynin (300µM) also reduced the LPA-induced FN adhesion by 47% (P<0.05) and 59% (P<0.05), respectively. Using confocal microscopy, we observed that blockade of LPA signaling, with Ki16425, reduced ROS by 45% (P<0.05), to levels similar to control VSMC unexposed to LPA. In intact isolated arterioles, LPA (2µM) exposure augmented the myogenic constriction response to step increases in intraluminal pressure (between 40-100mm Hg) by 71% (P<0.05). The blockade of LPA signaling, with Ki16425, decreased the LPA-enhanced myogenic constriction by 58% (P<0.05). Similarly, blockade of LPA-induced ROS release with tempol or gp91 ds-tat decreased the LPA-enhanced myogenic constriction by 56% (P<0.05) and 55% (P<0.05), respectively. These results indicate that, in VSMC, LPA-induced integrin activation involves the G-protein coupled receptors LPAR1 and LPAR3, and the production of ROS, and that LPA may play an important role in the control of myogenic behavior in resistance vessels through ROS modulation of integrin activity