The mechanisms by which active neurons, via astrocytes, rapidly signal intracerebral arterioles to dilate remain obscure. Here we show that modest elevation of extracellular potassium (K+) activated inward rectifier K+ (Kir) channels and caused membrane potential hyperpolarization in smooth muscle cells (SMCs) of intracerebral arterioles and, in cortical brain slices, induced Kir-dependent vasodilation and suppression of SMC intracellular calcium (Ca2+) oscillations. Neuronal activation induced a rapid (<2 s latency) vasodilation that was greatly reduced by Kir channel blockade and completely abrogated by concurrent cyclooxygenase inhibition. Astrocytic endfeet exhibited large-conductance, Ca2+-sensitive K+ (BK) channel currents that could be activated by neuronal stimulation. Blocking BK channels or ablating the gene encoding these channels prevented neuronally induced vasodilation and suppression of arteriolar SMC Ca2+, without affecting the astrocytic Ca2+ elevation. These results support the concept of intercellular K+ channel-to-K+ channel signaling, through which neuronal activity in the form of an astrocytic Ca2+ signal is decoded by astrocytic BK channels, which locally release K+ into the perivascular space to activate SMC Kir channels and cause vasodilation.

Hindlimb unloading of rats results in a diminished ability of skeletal muscle arterioles to constrict in vitro and elevate vascular resistance in vivo. The purpose of the present study was to determine whether alterations in the mechanical environment (i.e., reduced fluid pressure and blood flow) of the vasculature in hindlimb skeletal muscles from 2-wk hindlimb-unloaded (HU) rats induces a structural remodeling of arterial microvessels that may account for these observations. Transverse cross sections were used to determine media cross-sectional area (CSA), wall thickness, outer perimeter, number of media nuclei, and vessel luminal diameter of feed arteries and first-order (1A) arterioles from soleus and the superficial portion of gastrocnemius muscles. Endothelium-dependent dilation (ACh) was also determined. Media CSA of resistance arteries was diminished by hindlimb unloading as a result of decreased media thickness (gastrocnemius muscle) or reduced vessel diameter (soleus muscle). ACh-induced dilation was diminished by 2 wk of hindlimb unloading in soleus 1A arterioles, but not in gastrocnemius 1A arterioles. These results indicate that structural remodeling and functional adaptations of the arterial microvasculature occur in skeletal muscles of the HU rat; the data suggest that these alterations may be induced by reductions in transmural pressure (gastrocnemius muscle) and wall shear stress (soleus muscle).

Bone loss occurs as a consequence of exposure to microgravity. Using the hindlimb-unloaded rat to model spaceflight, this study had as its purpose to determine whether skeletal unloading and cephalic fluid shifts alter bone blood flow. We hypothesized that perfusion would be diminished in the hindlimb bones and increased in skeletal structures of the forelimbs and head. Using radiolabeled microspheres, we measured skeletal perfusion during control standing and after 10 min, 7 days, and 28 days of hindlimb unloading (HU). Femoral and tibial perfusion were reduced with 10 min of HU, and blood flow to the femoral shaft and marrow were further diminished with 28 days of HU. Correspondingly, the mass of femora (-11%, P < 0. 05) and tibiae (-6%, P < 0.1) was lowered with 28 days of HU. In contrast, blood flow to the skull, mandible, clavicle, and humerus was increased with 10 min HU but returned to control levels with 7 days HU. Mandibular (+10%, P < 0.05), clavicular (+18%, P < 0.05), and humeral (+8%, P < 0.1) mass was increased with chronic HU. The data demonstrate that simulated microgravity alters bone perfusion and that such alterations correspond to unloading-induced changes in bone mass. These results support the hypothesis that alterations in bone blood flow provide a stimulus for bone remodeling during periods of microgravity.

Hypertension, a major cardiovascular risk factor and cause of mortality worldwide, is thought to arise from primary renal abnormalities. However, the etiology of most cases of hypertension remains unexplained. Vascular tone, an important determinant of blood pressure, is regulated by nitric oxide, which causes vascular relaxation by increasing intracellular cGMP and activating cGMPdependent protein kinase I (PKGI). Here we show that mice with a selective mutation in the N-terminal protein interaction domain of PKGI␣ display inherited vascular smooth muscle cell abnormalities of contraction, abnormal relaxation of large and resistance blood vessels, and increased systemic blood pressure. Renal function studies and responses to changes in dietary sodium in the PKGI␣ mutant mice are normal. These data reveal that PKGI␣ is required for normal VSMC physiology and support the idea that high blood pressure can arise from a primary abnormality of vascular smooth muscle cell contractile regulation, suggesting a new approach to the diagnosis and therapy of hypertension and cardiovascular diseases.cyclic nucleotides ͉ hypertension ͉ nitric oxide ͉ vascular biology ͉ vascular smooth muscle E levated blood pressure is a major risk factor for cardiovascular diseases and is responsible for widespread morbidity and mortality (1). Blood pressure is regulated by a variety of complex neurohumoral and mechanical signals that together determine systemic vascular tone and resistance (2, 3). The prevailing model for elevated blood pressure states that renal abnormalities of sodium handling cause volume expansion, increased systemic vascular resistance, and hypertension, and a large number of physiologic and genetic studies support this model and the central role of the renal renin-angiotensinaldosterone system in blood pressure regulation (4-8). Changes in vascular morphology and tone can increase vascular resistance and blood pressure (5), but the hypothesis that primary abnormalities of vascular smooth muscle tone can cause hypertension has not been sufficiently tested (6).Vascular smooth muscle contraction is initiated by both calcium-dependent and -independent mechanisms. Increases in intracellular calcium from receptor-or ion channel-activated pathways (2) lead to activation of myosin light chain kinase, which phosphorylates myosin light chains, activating myosin ATPase and increasing vascular smooth muscle cell (VSMC) contraction and vascular tone. The central calcium-independent pathway regulating VSMC tension is mediated by the GTPase RhoA and Rho kinase, which promote VSMC differentiation, stress fiber formation, and contraction, also increasing vascular tone (2, 7). Conversely, VSMC relaxation is mediated by activation of myosin light chain phosphatase (MLCP), which dephosphorylates myosin light chains to cause relaxation. The relative proportion of phosphorylated and dephosphorylated myosin light chains thus determines the state of VSMC tone (reviewed in ref.2). Nitric oxide, the most important endogenous vasodilator, cause...

Hindlimb unloading (HU) of rats induces a cephalic shift in body fluids. We hypothesized that the putative increase in cranial fluid pressure and decrease in peripheral fluid pressure would alter the morphology of resistance arteries from 2-wk HU male Sprague-Dawley rats. To test this hypothesis, the cerebral basilar, mesenteric, and splenic arteries were removed from control (C) and HU animals. The vessels were cannulated, and luminal pressure was set to 60 cmH(2)O. The resistance arteries were then relaxed with 10(-4) M nitroprusside, fixed, and cut into transverse cross sections (5 microm thick). Media cross-sectional area (CSA), intraluminal CSA, media layer thickness, vessel outer perimeter, and media nuclei number were determined. In the basilar artery, both media CSA (HU 17, 893 +/- 2,539 microm(2); C 12,904 +/- 1,433 microm(2)) and thickness (HU 33.9 +/- 4.1 microm; C 22.3 +/- 3.2 microm) were increased with hindlimb unloading (P < 0.05), intraluminal CSA decreased (HU 7,816 +/- 3,045 microm(2); C 13,469 +/- 5,500 microm(2)) (P < 0.05), and vessel outer perimeter and media nuclei number were unaltered. There were no differences in mesenteric or splenic resistance artery morphology between HU and C rats. These findings suggest that hindlimb unloading-induced increases in cephalic arterial pressure and, correspondingly, increases in circumferential wall stress result in the hypertrophy of basilar artery smooth muscle cells.