We hypothesized that CO2 and H+ stimulate capillaries and arterioles to produce local and conducted vasodilations required to coordinate the distribution of blood flow to contracting skeletal muscle fibers. CO2 and H+ independently and in combination were applied to 2A arterioles (first branch order from the 1A feed arteriole) and capillaries of the in situ, blood-perfused hamster cremaster muscle. The resulting local and conducted vasodilations were measured. H+ (pH: 7.2-6.6) and CO2 (5% and 10%) applied to the vascular network induced 2A arteriolar vasodilations, while 15% CO2 produced vasoconstriction. Localized application of H+ produced 2A arteriolar vasodilation, while 15% CO2 resulted in a variable response. Simultaneous application of CO2 and H+ did not result in the predicted additive effects. Application of CO2 and H+ alone or combined on arterioles or capillaries did not induce a conducted response. CO2 and H+ produce arteriolar vasodilation but, critically, cannot stimulate the spread of vasodilation throughout the network, thus limiting their ability to coordinating blood flow to contracting skeletal muscle fibers. Given their potential for interaction, the importance of CO2 and H+ may lie in their ability to modify the effects of other vasodilators.

Oxidative stress is a central event linked with endothelial dysfunction and inflammation in several vascular pathologies, marked by over-production of ROS and concomitant decreases in antioxidants, for example GSH. Here, we distinguish endothelial oxidative stress regulation and associated functional disparities in the two main vascular conduits, (arteries and veins) following decreases in GSH. MAECs and VCECs were used as models of arterial and venular endothelium, respectively, and BSO (0-100μmol/L) was used to indirectly increase cellular oxidative stress. Inflammatory responses were measured using immune cell attachment and immunoblotting for endothelial cell adhesion molecule (ICAM-1, VCAM-1) expression, altered cell proliferation, and wound healing. MAECs and VCECs exhibited differential responses to oxidative stress produced by GSH depletion with VCECs exhibiting greater sensitivity to oxidative stress. Compared to MAECs, VCECs showed a significantly increased inflammatory profile and a decreased proliferative phenotype in response to decreases in GSH levels. Arterial and venous endothelial cells exhibit differential responses to oxidant stress, and decreases in GSH:GSSG are more exacerbated in venous endothelial cells. Specific pathogenesis in these vascular conduits, with respect to oxidant stress handling, warrants further study, especially considering surgical interventions such as Coronary artery bypass grafting that use both interchangeably.

AKI is a common complication of sepsis and is significantly associated with mortality. Sepsis accounts for more than 50% of the cases of AKI, with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex, but there is emerging evidence that, at least in the first 48hours, the defects may be functional rather than structural in nature. For example, septic AKI is associated with an absence of histopathological changes, but with microvascular abnormalities and tubular stress. In this context, renal medullary hypoxia due to redistribution of intra-renal perfusion is emerging as a critical mediator of septic AKI. Clinically, vasopressor drugs remain the cornerstone of therapy for maintenance of blood pressure and organ perfusion. However, in septic AKI, there is insensitivity to vasopressors such as norepinephrine, leading to persistent hypotension and organ failure. Vasopressin, angiotensin II, and, paradoxically, α2 -adrenergic receptor agonists (clonidine and dexmedetomidine) may be feasible adjunct therapies for catecholamine-resistant vasodilatory shock. In this review, we outline the recent progress made in understanding how these drugs may influence the renal microcirculation, which represents a crucial step toward developing better approaches for the circulatory management of patients with septic AKI.

Changes in microvascular perfusion have been reported in many diseases, yet the functional significance of altered perfusion is often difficult to determine. This is partly because commonly used techniques for perfusion measurement often rely on either indirect or by-hand approaches. We developed and validated a fully automated software technique to measure microvascular perfusion in videos acquired by fluorescence microscopy in the mouse gastrocnemius. Acute perfusion responses were recorded following intravenous injections with phenylephrine, SNP, or saline. Software-measured capillary flow velocity closely correlated with by-hand measured flow velocity (R2 =0.91, P<0.0001). Software estimates of capillary hematocrit also generally agreed with by-hand measurements (R2 =0.64, P<0.0001). Detection limits range from 0 to 2000μm/s, as compared to an average flow velocity of 326±102μm/s (mean±SD) at rest. SNP injection transiently increased capillary flow velocity and hematocrit and made capillary perfusion more steady and homogenous. Phenylephrine injection had the opposite effect in all metrics. Saline injection transiently decreased capillary flow velocity and hematocrit without influencing flow distribution or stability. All perfusion metrics were temporally stable without intervention. These results demonstrate a novel and sensitive technique for reproducible, user-independent quantification of microvascular perfusion.

Early maternal vascular adaptations to pregnancy are predominantly driven by changes in vascular tone, reactivity, and remodeling. Failure of the maternal systemic vasculature to adapt sufficiently can lead to serious complications of pregnancy. The hormone relaxin is widely recognized for its contribution to the essential renal and systemic hemodynamic adaptations in early pregnancy through direct actions on the maternal vasculature. Studies in relaxin gene knockout mice revealed that endogenous relaxin is not only a "pregnancy hormone" but has pleiotropic actions in various tissues in males and non-pregnant females. There is strong interest in relaxin's actions in the vasculature and its utility in the treatment of vascular diseases. Relaxin treatment in rodents for 2-5days or acute intravenous injection enhances endothelium-dependent relaxation and decreases myogenic tone in resistance arteries. These vascular actions are prolonged, even in the absence of circulating relaxin, and are underpinned by the production of endothelium-derived relaxing factors including nitric oxide, endothelium-derived hyperpolarization, and prostacyclin. Relaxin is also capable of remodeling the vascular wall in a variety of blood vessels in disease conditions. Lessons learned in pregnancy research have aided studies investigating the potential therapeutic potential of relaxin in cardiovascular disease.

The effect of NO on smooth muscle cell contractility is crucial in regulating vascular tone, blood flow, and O2 delivery. Quantitative predictions for interactions between the NO production rate and the myogenic response for microcirculatory blood vessels are lacking. We developed a computational model of a branching microcirculatory network with four representative classes of resistance vessels to predict the effect of endothelium-derived NO on the microvascular pressure-flow response. Our model links vessel scale biotransport simulations of NO and O2 delivery to a mechanistic model of autoregulation and myogenic tone in a simplified microcirculatory network. The model predicts that smooth muscle cell NO bioavailability significantly contributes to resting vascular tone of resistance vessels. Deficiencies in NO seen during hypoxia or ischemia lead to a decreased vessel diameter for all classes at a given intravascular pressure. At the network level, NO deficiencies lead to an increase in pressure drop across the vessels studied, a downward shift in the pressure-flow curve, and a decrease in the effective range of the autoregulatory response. Our model predicts the steady state and transient behavior of resistance vessels to perturbations in blood pressure, including effects of NO bioavailability on vascular regulation.

Our aging population is set to grow considerably in the coming decades. In fact, the number of individuals older than 65years will double by 2050. This projected increase in people living with extended life expectancy represents an inevitable upsurge in the presentation of age-related pathologies. However, our current understanding of the impact of aging on a number of biological processes is unfortunately inadequate. Cardiovascular, cerebrovascular, and neurodegenerative diseases are particularly prevalent in the elderly population. Intriguingly, these pathologies are all associated with vascular dysfunction, suggesting that the process of aging can induce structural and functional impairments in vascular networks. Together with elevated cell senescence, pre-existing comorbidities, and the emerging concept of age-associated inflammatory imbalance, impaired vascular functions can significantly increase one's risk in acquiring age-related diseases. In this short review, we highlight some current clinical and experimental evidence of how biological aging contributes to three vascular-associated pathologies: atherosclerosis, stroke, and Alzheimer's disease.

Pericytes are specialized perivascular cells embedded within the basement membrane. These cells envelope the abluminal surface of endothelial cells and promote microvessel homeostasis. Recent discoveries of unique pericyte functions, particularly in neural tissues, underscore the need for overcoming existing challenges in establishing a functionally validated pericyte cell line. Here, we present methodologies for addressing these challenges as well as an embryonic pericyte cell line for use with in vitro and ex vivo experimental models. We isolated an enriched population of NG2:DsRed+ pericytes from E12.5 mice. This pericyte cell line was compared to MEFs with respect to gene expression, cell morphology and migration, and engagement with endothelial cells during junction stabilization and angiogenesis. NG2+ pericytes displayed gene expression patterns, cell morphology, and 2D migration behaviors distinct from MEFs. In three different vessel formation models, pericytes from this line migrated to and incorporated into developing vessels. When co-cultured with HUVECs, these pericytes stimulated more robust VE-Cadherin junctions between HUVECs as compared to MEFs, as well as contributed to HUVEC organization into primitive vascular structures. Our data support use of this pericyte cell line in a broad range of models to further understand pericyte functionality during normal and pathological conditions.

Electrical signaling along the endothelium underlies spreading vasodilation and blood flow control. We use mathematical modeling to determine the electrical properties of the endothelium and gain insight into the biophysical determinants of electrical conduction. Electrical conduction data along endothelial tubes (40μm wide, 2.5mm long) isolated from mouse skeletal muscle resistance arteries were analyzed using cable equations and a multicellular computational model. Responses to intracellular current injection attenuate with an axial length constant (λ) of 1.2-1.4mm. Data were fitted to estimate the axial (ra ; 10.7MΩ/mm) and membrane (rm ; 14.5MΩ∙mm) resistivities, EC membrane resistance (Rm ; 12GΩ), and EC-EC coupling resistance (Rgj ; 4.5MΩ) and predict that stimulation of ≥30 neighboring ECs is required to elicit 1 mV of hyperpolarization at distance = 2.5 mm. Opening Ca2+ -activated K+ channels (KCa ) along the endothelium reduced λ by up to 55%. High Rm makes the endothelium sensitive to electrical stimuli and able to conduct these signals effectively. Whereas the activation of a group of ECs is required to initiate physiologically relevant hyperpolarization, this requirement is increased by myoendothelial coupling and KCa activation along the endothelium inhibits conduction by dissipating electrical signals.