It is widely accepted that regular physical activity is beneficial for cardiovascular health. Frequent exercise is robustly associated with a decrease in cardiovascular mortality as well as the risk of developing cardiovascular disease. Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Animal models of exercise show that repeated physical activity suppresses atherogenesis and increases the availability of vasodilatory mediators such as nitric oxide. Exercise has also been found to have beneficial effects on the heart. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy. Both cardiac and vascular changes have been linked to a variety of changes in tissue metabolism and signaling, although our understanding of the contribution of the underlying mechanisms remains incomplete. Even though moderate levels of exercise have been found to be consistently associated with a reduction in cardiovascular disease risk, there is evidence to suggest that continuously high levels of exercise (e.g., marathon running) could have detrimental effects on cardiovascular health. Nevertheless, a specific dose response relationship between the extent and duration of exercise and the reduction in cardiovascular disease risk and mortality remains unclear. Further studies are needed to identify the mechanisms that impart cardiovascular benefits of exercise in order to develop more effective exercise regimens, test the interaction of exercise with diet, and develop pharmacological interventions for those unwilling or unable to exercise.

Rationale Endothelial progenitor cells (EPCs) respond to SDF-1 through receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes induced EPCs dysfunction remains unknown. Objective To determine the role of SDF-1 receptors in diabetic EPCs dysfunction. Methods and Results CXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, while up-regulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein (ox-LDL) or high glucose (HG) also reduced CXCR7 expression, impaired tube formation and increased oxidative stress and apoptosis. The damaging effects of ox-LDL or HG were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus (CXCR7-EPCs) but not in EPCs transduced with control lentivirus (Null-EPCs). Most importantly, CXCR7-EPCs were superior to Null-EPCs for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that ox-LDL or HG inhibited Akt and GSK-3β phosphorylation, nuclear export of Fyn and nuclear localization of Nrf2, blunting Nrf2 downstream target genes HO-1, NQO-1 and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in CXCR7-EPCs. Furthermore, inhibition of PI3K/Akt prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo. Conclusions Elevated expression of CXCR7 enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by an Akt/GSK-3β/Fyn pathway via increased activity of Nrf2.

Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects of increased glucose (hyperglycemia) on L-type CaV1.2 channels. In murine arterial myocytes, kinase-dependent mechanisms mediate the increase in CaV1.2 activity in response to increased extracellular glucose. We identified a subpopulation of the CaV1.2 channel pore-forming subunit (α1C) within nanometer proximity of protein kinase A (PKA) at the sarcolemma of murine and human arterial myocytes. This arrangement depended upon scaffolding of PKA by an A-kinase anchoring protein 150 (AKAP150) in mice. Glucose-mediated increases in CaV1.2 channel activity were associated with PKA activity, leading to α1C phosphorylation at Ser1928. Compared to arteries from low-fat diet (LFD)–fed mice and nondiabetic patients, arteries from high-fat diet (HFD)–fed mice and from diabetic patients had increased Ser1928 phosphorylation and CaV1.2 activity. Arterial myocytes and arteries from mice lacking AKAP150 or expressing mutant AKAP150 unable to bind PKA did not exhibit increased Ser1928 phosphorylation and CaV1.2 current density in response to increased glucose or to HFD. Consistent with a functional role for Ser1928 phosphorylation, arterial myocytes and arteries from knockin mice expressing a CaV1.2 with Ser1928 mutated to alanine (S1928A) lacked glucose-mediated increases in CaV1.2 activity and vasoconstriction. Furthermore, the HFD-induced increases in CaV1.2 current density and myogenic tone were prevented in S1928A knockin mice. These findings reveal an essential role for α1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes.

Rationale Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes may arise from impaired large conductance Ca2+-activated K+ (BKCa) channel function. The scaffolding protein AKAP150 is a key regulator of calcineurin (CaN), a phosphatase known to modulate expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes is unknown. Objective To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes. Methods and Results We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/NFATc3 activation, and resistance artery constriction in hyperglycemic animals on high fat diet (HFD). Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. D-glucose-dependent suppression of BKCa channel β1 subunits required Ca2+ influx via voltage-gated L-type Ca2+ channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, HFD mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits, and attenuated HFD-induced elevation in arterial blood pressure. Conclusions Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes.

Nystoriak MA, O'Connor KP, Sonkusare SK, Brayden JE, Nelson MT, Wellman GC. Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization. Am J Physiol Heart Circ Physiol 300: H803-H812, 2011. First published December 10, 2010 doi:10.1152 doi:10. /ajpheart.00760.2010 arterioles are morphologically and physiologically unique compared with pial arteries and arterioles. The ability of subarachnoid hemorrhage (SAH) to induce vasospasm in large-diameter pial arteries has been extensively studied, although the contribution of this phenomenon to patient outcome is controversial. Currently, little is known regarding the impact of SAH on parenchymal arterioles, which are critical for regulation of local and global cerebral blood flow. Here diameter, smooth muscle intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i), and membrane potential measurements were used to assess the function of intact brain parenchymal arterioles isolated from unoperated (control), sham-operated, and SAH model rats. At low intravascular pressure (5 mmHg), membrane potential and [Ca 2ϩ ]i were not different in arterioles from control, sham-operated, and SAH animals. However, raising intravascular pressure caused significantly greater membrane potential depolarization, elevation in [Ca 2ϩ ]i, and constriction in SAH arterioles. This SAH-induced increase in [Ca 2ϩ ]i and tone occurred in the absence of the vascular endothelium and was abolished by the L-type voltage-dependent calcium channel (VDCC) inhibitor nimodipine. Arteriolar [Ca 2ϩ ]i and tone were not different between groups when smooth muscle membrane potential was adjusted to the same value. Protein and mRNA levels of the L-type VDCC CaV1.2 were similar in parenchymal arterioles isolated from control and SAH animals, suggesting that SAH did not cause VDCC upregulation. We conclude that enhanced parenchymal arteriolar tone after SAH is driven by smooth muscle membrane potential depolarization, leading to increased L-type VDCC-mediated Ca 2ϩ influx.voltage-dependent calcium channels; vascular smooth muscle; cerebral blood flow; endothelium; ion channels CEREBRAL BLOOD FLOW IS REGULATED by the diameter of resistance arteries and arterioles both on the surface of the brain and within the brain parenchyma. Parenchymal arterioles, unlike pial arteries and arterioles, lack extrinsic innervation and are encased by astrocytic processes ("endfeet") (17, 27). The close association of this microvasculature with astrocytic endfeet is essential for functional hyperemia, whereby focal increases in neuronal activity are coupled to vasodilation of nearby arterioles and increased blood flow (6,14,27,45). In addition to their role in neurovascular coupling, parenchymal arterioles also contribute significantly to autoregulation of global cerebral blood flow and account for ϳ40% of total cerebral vascular resistance (12 (1,13,19,32,44). Recent work has established that pressuredependent constriction, or myogeni...

The L-type Ca2+ channel Cav1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving β-adrenergic receptors (βARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylates Ser1928 in Cav1.2 in vitro and in vivo, including in rodents and humans. However, S1928A knock-in (KI) mice have normal PKA-mediated L-type channel regulation in the heart, indicating that Ser1928 is not required for regulation of cardiac Cav1.2 by PKA in this tissue. We report that augmentation of L-type currents by PKA in neurons was absent in S1928A KI mice. Furthermore, S1928A KI mice failed to induce long-term potentiation in response to prolonged theta-tetanus (PTT-LTP), a form of synaptic plasticity that requires Cav1.2 and enhancement of its activity by the β2-adrenergic receptor (β2AR)–cAMP–PKA cascade. Thus, there is an unexpected dichotomy in the control of Cav1.2 by PKA in cardiomyocytes and hippocampal neurons.

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Calcium (Ca2+) plays a central role in excitation, contraction, transcription, and proliferation of vascular smooth muscle cells (VSMs). Precise regulation of intracellular Ca2+concentration ([Ca2+]i) is crucial for proper physiological VSM function. Studies over the last several decades have revealed that VSMs express a variety of Ca2+-permeable channels that orchestrate a dynamic, yet finely tuned regulation of [Ca2+]i. In this review, we discuss the major Ca2+-permeable channels expressed in VSM and their contribution to vascular physiology and pathology.