Vascular mechanotransduction.

This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), including their sensing of mechanical stimuli and transduction of mechanical signals that result in the acute functional modulation and longer-term transcriptomic and epigenetic regulation of blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures and receptors, and junction proteins. The mechanosignaling pathways presented include the cytoskeleton, integrins, extracellular matrix, and intracellular signaling molecules. These are followed by discussions on mechanical regulation of transcriptome and epigenetics, relevance of mechanotransduction to health and disease, and interactions between VSMCs and ECs. Throughout this review, we offer suggestions for specific topics that require further understanding. In the closing section on conclusions and perspectives, we summarize what is known and point out the need to treat the vasculature as a system, including not only VSMCs and ECs but also the extracellular matrix and other types of cells such as resident macrophages and pericytes, so that we can fully understand the physiology and pathophysiology of the blood vessel as a whole, thus enhancing the comprehension, diagnosis, treatment, and prevention of vascular diseases.

Unraveling the Gordian knot of coronary pressure-flow autoregulation.

The coronary circulation has the inherent ability to maintain myocardial perfusion constant over a wide range of perfusion pressures. The phenomenon of pressure-flow autoregulation is crucial in response to flow-limiting atherosclerotic lesions which diminish coronary driving pressure and increase risk of myocardial ischemia and infarction. Despite well over half a century of devoted research, understanding of the mechanisms responsible for autoregulation remains one of the most fundamental and contested questions in the field today. The purpose of this review is to highlight current knowledge regarding the complex interrelationship between the pathways and mechanisms proposed to dictate the degree of coronary pressure-flow autoregulation. Our group recently likened the intertwined nature of the essential determinants of coronary flow control to the symbolically unsolvable "Gordian knot". To further efforts to unravel the autoregulatory "knot", we consider recent challenges to the local metabolic and myogenic hypotheses and the complicated dynamic structural and functional heterogeneity unique to the heart and coronary circulation. Additional consideration is given to interrogation of putative mediators, role of K+ and Ca2+ channels, and recent insights from computational modeling studies. Improved understanding of how specific vasoactive mediators, pathways, and underlying disease states influence coronary pressure-flow relations stands to significantly reduce morbidity and mortality for what remains the leading cause of death worldwide.

In vivo pressure-flow relation of human cutaneous vessels following prolonged iterative exposures to hypergravity.

The study examined intra- and interlimb variations in cutaneous vessel responsiveness to acute and repeated transmural pressure elevations. In 11 healthy men, red blood cell flux was assessed via laser-Doppler flowmetry on both glabrous and nonglabrous skin regions of an arm (finger and forearm) and leg (toe and lower leg), across a wide range of stepwise increasing distending pressures imposed in the vessels of each limb separately. The pressure-flux cutaneous responses were evaluated before and after 5 wk of intermittent (40 min, 3 sessions per week) exposures to hypergravity (∼2.6-3.3 G; G training). Before and after G training, forearm and lower leg blood flux were relatively stable up to ∼210 and ∼240 mmHg distending pressures, respectively; and then they increased two- to threefold (P < 0.001). Finger blood flux dropped promptly (P < 0.001), regardless of the G training (P = 0.64). At ≤120-mmHg distending pressures, toe blood flux enhanced by ∼40% (P ≤ 0.05); the increase was augmented after the G training (P = 0.01). At high distending pressures, toe blood flux dropped by ∼70% in both trials (P < 0.001). The present results demonstrate that circulatory autoregulation is more pronounced in glabrous skin than in nonglabrous skin, and in nonglabrous sites of the leg than in those of the arm. Repetitive high-sustained gravitoinertial stress does not modify the pressure-flow relationship in the dependent skin vessels of the arm nor in the nonglabrous sites of the lower leg. Yet it may partly inhibit the myogenic responsiveness of the toe's glabrous skin.

Luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, reverses cerebrovascular dysfunction and cognitive impairments in 18-mo-old diabetic animals.

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved are not well understood. We previously discovered that hyperglycemia induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-mo-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reducing plasma glucose with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-mo-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.NEW & NOTEWORTHY This study demonstrates that luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, improved CBF autoregulation in association with reduced vascular oxidative stress and AGEs production in the cerebrovasculature of 18-mo-old DM rats. SGLT2i also prevented BBB leakage, impaired functional hyperemia, neurodegeneration, and cognitive impairment seen in DM rats. Luseogliflozin did not have direct constrictive effects on VSMCs and MCAs isolated from normal rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.

Advanced Maternal Age Impairs Uterine Artery Adaptations to Pregnancy in Rats.

Advanced maternal age (≥35 years) is associated with pregnancy complications. Aging impairs vascular reactivity and increases vascular stiffness. We hypothesized that uterine artery adaptations to pregnancy are impaired with advanced age. Uterine arteries of nonpregnant and pregnant (gestational day 20) young (4 months) and aged (9 months; ~35 years in humans) Sprague-Dawley rats were isolated. Functional (myogenic tone, n = 6−10/group) and mechanical (circumferential stress-strain, n = 10−24/group) properties were assessed using pressure myography and further assessment of elastin and collagen (histology, n = 4−6/group), and matrix metalloproteinase-2 (MMP-2, zymography, n = 6/group). Aged dams had worse pregnancy outcomes, including smaller litters and fetal weights (both p < 0.0001). Only in arteries of pregnant young dams did higher pressures (>100 mmHg) cause forced vasodilation. Across the whole pressure range (4−160 mmHg), myogenic behavior was enhanced in aged vs. young pregnant dams (p = 0.0010). Circumferential stress and strain increased with pregnancy in young and aged dams (p < 0.0001), but strain remained lower in aged vs. young dams (p < 0.05). Arteries from young nonpregnant rats had greater collagen:elastin ratios than the other groups (p < 0.05). In aged rats only, pregnancy increased MMP-2 active capacity. Altered functional and structural vascular adaptations to pregnancy may impair fetal growth and development with advanced maternal age.

Mechanotransduction in gastrointestinal smooth muscle cells: role of mechanosensitive ion channels.

Mechanosensation, the ability to properly sense mechanical stimuli and transduce them into physiologic responses, is an essential determinant of gastrointestinal (GI) function. Abnormalities in this process result in highly prevalent GI functional and motility disorders. In the GI tract, several cell types sense mechanical forces and transduce them into electrical signals, which elicit specific cellular responses. Some mechanosensitive cells like sensory neurons act as specialized mechanosensitive cells that detect forces and transduce signals into tissue-level physiological reactions. Nonspecialized mechanosensitive cells like smooth muscle cells (SMCs) adjust their function in response to forces. Mechanosensitive cells use various mechanoreceptors and mechanotransducers. Mechanoreceptors detect and convert force into electrical and biochemical signals, and mechanotransducers amplify and direct mechanoreceptor responses. Mechanoreceptors and mechanotransducers include ion channels, specialized cytoskeletal proteins, cell junction molecules, and G protein-coupled receptors. SMCs are particularly important due to their role as final effectors for motor function. Myogenic reflex-the ability of smooth muscle to contract in response to stretch rapidly-is a critical smooth muscle function. Such rapid mechanotransduction responses rely on mechano-gated and mechanosensitive ion channels, which alter their ion pores' opening in response to force, allowing fast electrical and Ca2+ responses. Although GI SMCs express a variety of such ion channels, their identities remain unknown. Recent advancements in electrophysiological, genetic, in vivo imaging, and multi-omic technologies broaden our understanding of how SMC mechano-gated and mechanosensitive ion channels regulate GI functions. This review discusses GI SMC mechanosensitivity's current developments with a particular emphasis on mechano-gated and mechanosensitive ion channels.

Differential responsiveness of glabrous and nonglabrous skin to local transmural pressure elevations: impact of 5 weeks of iterative local pressure loading.

We examined the in vivo pressure-flow relationship in human cutaneous vessels during acute and repeated elevations of local transmural pressure. In 10 healthy men, red blood cell flux was monitored simultaneously on the nonglabrous skin of the forearm and the glabrous skin of a finger during a vascular pressure provocation, wherein the blood vessels of an arm were exposed to a wide range of stepwise increasing distending pressures. Forearm skin blood flux was relatively stable at slight and moderate elevations of distending pressure, whereas it increased approximately three- to fourfold at the highest levels (P = 0.004). Finger blood flux, on the contrary, dropped promptly and consistently throughout the provocation (P < 0.001). Eight of the subjects repeated the provocation trial after a 5-wk pressure-training regimen, during which the vasculature in one arm was exposed intermittently (40 min, 3 times/wk) to increased transmural pressure (from +65 mmHg week 1 to +105 mmHg week 5). The training regimen diminished the pressure-induced increase in forearm blood flux by ∼34% (P = 0.02), whereas it inhibited the reduction in finger blood flux (P < 0.001) in response to slight and moderate distending pressure elevations. The present findings demonstrate that during local pressure perturbations, the cutaneous autoregulatory function is accentuated in glabrous compared with in the nonglabrous skin regions. Prolonged intermittent regional exposures to augmented intravascular pressure blunt the responsiveness of the glabrous skin but enhance arteriolar pressure resistance in the nonglabrous skin.

20-HETE-promoted cerebral blood flow autoregulation is associated with enhanced pericyte contractility.

We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, HET0016, but restored with 20-HETE analog WIT003. Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and were rescued by WIT003. The myogenic response of the PA was abolished in SS and was restored in SS.BN5 and SS.Cyp4a1 rats. HET0016 enhanced CBF and impaired its autoregulation in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in controlling cerebral vascular function.

A Mutation in γ-Adducin Impairs Autoregulation of Renal Blood Flow and Promotes the Development of Kidney Disease.

BACKGROUND: The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ-adducin (ADD3), a cytoskeletal protein encoded by Add3. METHODS: We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats. RESULTS: This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats-a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from Add3 transgenic rats, those from FHH rats had elevated membrane expression of BKα and BK channel current. FHH and Add3 knockout rats exhibited impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. Add3 transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension. CONCLUSIONS: This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.

Impaired renal hemodynamics and glomerular hyperfiltration contribute to hypertension-induced renal injury.

Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1BN congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1BNAdd3KO (Add3KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in Add3KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus Add3KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in Add3KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in Add3KO rats. The degree of renal injury was greater in Add3KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in Add3KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive Add3KO rats.

Influence of connexin45 on renal autoregulation.

Renal autoregulation is mediated by the myogenic response and tubuloglomerular feedback (TGF) working in concert to maintain renal blood flow and glomerular filtration rate despite fluctuations in renal perfusion pressure. Intercellular communication through gap junctions may play a role in renal autoregulation. We examine if one of the building blocks in gap junctions, connexin45 (Cx45), which is expressed in vascular smooth muscle cells, has an influence on renal autoregulatory efficiency. The isolated perfused juxtamedullary nephron preparation was used to measure afferent arteriolar diameter changes in response to acute changes in renal perfusion pressure. In segmental arteries, pressure myography was used to study diameter changes in response to pressure changes. Wire myography was used to study vasoconstrictor and vasodilator responses. A mathematical model of the vascular wall was applied to interpret experimental data. We found a significant reduction in the afferent arteriolar constriction in response to acute pressure increases in Cx45 knockout (KO) mice compared with wild-type (WT) mice. Abolition of TGF caused a parallel upward shift in the autoregulation curve of WT animals but had no effect in KO animals, which is compatible with TGF providing a basal tonic contribution in afferent arterioles whereas Cx45 KO animals were functionally papillectomized. Analysis showed a shift toward lower stress sensitivity in afferent arterioles from Cx45 KO animals, indicating that the absence of Cx45 may also affect myogenic properties. Finally, loss of Cx45 in vascular smooth muscle cells appeared to associate with a change in both structure and passive properties of the vascular wall.

Sex differences in the structure and function of rat middle cerebral arteries.

Epidemiological studies demonstrate that there are sex differences in the incidence, prevalence, and outcomes of cerebrovascular disease (CVD). The present study compared the structure and composition of the middle cerebral artery (MCA), neurovascular coupling, and cerebrovascular function and cognition in young Sprague-Dawley (SD) rats. Wall thickness and the inner diameter of the MCA were smaller in females than males. Female MCA exhibited less vascular smooth muscle cells (VSMCs), diminished contractile capability, and more collagen in the media, and a thicker internal elastic lamina with fewer fenestrae compared with males. Female MCA had elevated myogenic tone, lower distensibility, and higher wall stress. The stress/strain curves shifted to the left in female vessels compared with males. The MCA of females failed to constrict compared with a decrease of 15.5 ± 1.9% in males when perfusion pressure was increased from 40 to 180 mmHg. Cerebral blood flow (CBF) rose by 57.4 ± 4.4 and 30.1 ± 3.1% in females and males, respectively, when perfusion pressure increased from 100 to 180 mmHg. The removal of endothelia did not alter the myogenic response in both sexes. Functional hyperemia responses to whisker-barrel stimulation and cognition examined with an eight-arm water maze were similar in both sexes. These results demonstrate that there are intrinsic structural differences in the MCA between sexes, which are associated with diminished myogenic response and CBF autoregulation in females. The structural differences do not alter neurovascular coupling and cognition at a young age; however, they might play a role in the development of CVD after menopause.NEW & NOTEWORTHY Using perfusion fixation of the middle cerebral artery (MCA) in calcium-free solution at physiological pressure and systematically randomly sampling the sections prepared from the same M2 segments of MCA, we found that there are structural differences that are associated with altered cerebral blood flow (CBF) autoregulation but not neurovascular coupling and cognition in young, healthy Sprague-Dawley (SD) rats. Understanding the intrinsic differences in cerebrovascular structure and function in males and females is essential to develop new pharmaceutical treatments for cerebrovascular disease (CVD).

Modeling acute blood flow responses to a major arterial occlusion.

OBJECTIVE: The development of earlier and less invasive treatments for peripheral arterial disease requires a more complete understanding of vascular responses following a major arterial occlusion. A mechanistic model of the vasculature of the rat hindlimb is developed to predict acute (immediate) changes in vessel diameters and smooth muscle tone following femoral arterial occlusion. METHODS: Vascular responses of collateral arteries and distal arterioles to changes in pressure, shear stress, and metabolism are assessed before and after occlusion. The effects of exercise are also simulated and compared with venous flow measurements from WKY rats. RESULTS: The model identifies collateral arteries as the primary contributors to flow compensation following occlusion. Increasing the number of capillaries has minimal effect on blood flow while increasing the number of collateral arteries significantly increases flow, since the primary site of resistance shifts upstream to the collateral arteries following occlusion. Despite significant collateral dilation, calf flow remains below pre-occlusion levels and the deficit becomes more severe with increased activity. CONCLUSIONS: Although unable to compensate fully for an occlusion, the model demonstrates the importance of the shear response in collateral arteries and the metabolic response in the distal microcirculation in acute adaptations to a major arterial occlusion.

Stimulation of autophagy improves vascular function in the mesenteric arteries of type 2 diabetic mice.

NEW FINDINGS: What is the central question of this study? What is the role of autophagy in vascular dysfunction in type 2 diabetes? What is the main finding and its importance? Autophagy is decreased in the mesenteric arteries of type 2 diabetic mice, and stimulation of autophagy using rapamycin and trehalose improves vascular function, which is associated with normalization of myogenic response and endothelium-dependent relaxation. ABSTRACT: Vascular dysfunction is a major complication in type 2 diabetes (T2D). It has been suggested that dysregulation of autophagy is associated with various cardiovascular diseases. However, the relationship between autophagy and vascular dysfunction in T2D remains unclear. Thus, we examined whether reduced autophagy is involved in vascular dysfunction and whether stimulation of autophagy could improve vascular function in diabetes. Ten- to twelve-week-old male type 2 diabetic (db- /db- ) mice and their control (db- /db+ ) mice were treated with rapamycin or trehalose. Mesenteric arteries (MAs) were mounted for arteriography and their diameter was measured. Western blot analysis and immunofluorescence staining were assessed. Myogenic response (MR) was significantly increased, whereas endothelium-dependent relaxation (EDR) was significantly attenuated in the MAs of diabetic mice. These results were associated with increased expression of LC3II, p62 and beclin-1 in diabetic mice. Treatment with autophagy stimulators significantly reduced the potentiation of MR and improved EDR in the diabetic mice. Furthermore, autophagy stimulation normalized expression of LC3II, p62 and beclin-1 in the diabetic mice. In addition, phosphorylation level of endothelial nitric oxide synthase was decreased in diabetic mice and was restored by rapamycin and trehalose. T2D impairs vascular function by dysregulated autophagy. Therefore, autophagy could be a potential target for overcoming diabetic microvascular complications.

Double deletion of calponin 1 and calponin 2 in mice decreases systemic blood pressure with blunted length-tension response of aortic smooth muscle.

Calponin is a family of actin filament-associated regulatory proteins. Among its three isoforms, calponin 1 is smooth muscle specific and calponin 2 is expressed in smooth muscle and certain non-muscle cells. Previous studies showed that calponin 1 knockout mice had detectable changes in the contractility of urogenital smooth muscle whereas other smooth muscles were less affected. To investigate the possibility that calponins 1 and 2 have overlapping functions in smooth muscle, we examined the effect of double knockout of calponin 1 and calponin 2 genes (Cnn1 and Cnn2) on smooth muscle functions. The results showed for the first time that calponin 1 and calponin 2 double knockout in mice does not cause lethality. The double knockout mice showed decreased systemic blood pressure, decreased force development and blunted length tension response in endothelial-removed aortic rings. A compensatory increase of calponin 1 was found in smooth muscle of Cnn2-/- mice but not vice versa. Cnn1-/- and Cnn2-/- double knockout aortic smooth muscle exhibits faster relaxation than that of wild type control. Double deletion or co-suppression of calponin 1 and calponin 2 in vascular smooth muscle to blunt myogenic response may present a novel approach to develop new treatment for hypertension.

Exercise training restores the myogenic response in skeletal muscle resistance arteries and corrects peripheral edema in rats with heart failure.

Impairment of the myogenic response can affect capillary hydrostatic pressure and contribute to peripheral edema and exercise intolerance, which are markers of heart failure (HF). The aim of this study was to assess the effects of exercise training (ET) on myogenic response in skeletal muscle resistance arteries and peripheral edema in HF rats, focusing on the potential signaling pathways involved in these adjustments. Male Wistar rats were submitted to either coronary artery occlusion or a sham-operated surgery. After 4 wk, an exercise test was performed, and the rats were divided into the following groups: untrained normal control (UNC) and untrained HF (UHF) and exercise- trained (on treadmill, 50-60% of maximal capacity) NC (TNC) and exercise-trained HF (THF). Caudal tibial artery (CTA) myogenic response was impaired in UHF compared with UNC, and ET restored this response in THF to NC levels and increased it in TNC. Rho kinase (ROCK) inhibitor abolished CTA myogenic response in the untrained and blunted it in exercise-trained groups. CTA-stored calcium (Ca2+) mobilization was higher in exercise-trained rats compared with untrained rats. The paw volume was higher in UHF rats, and ET decreased this response compared with UNC. Myogenic constriction was positively correlated with maximal running distance and negatively correlated with paw volume. The results demonstrate, for the first time, that HF impairs the myogenic response in skeletal muscle arteries, which contributes to peripheral edema in this syndrome. ET restores the myogenic response in skeletal muscle arteries improving Ca2+ sensitization and handling. Additionally, this paradigm also improves peripheral edema and exercise intolerance. NEW & NOTEWORTHY The novel and main finding of the present study is that moderate intensity exercise training restores the impaired myogenic response of skeletal muscle resistance arteries, exercise intolerance and peripheral edema in rats with heart failure. These results also show for the first time to our knowledge that exercise training improving calcium sensitization through the ROCK pathway and enhancing intracellular calcium handling could contribute to restoration of flow autoregulation to skeletal muscle in heart failure.

Pathophysiology of Cerebral Vascular Dysfunction in Pregnancy-Induced Hypertension.

PURPOSE OF REVIEW: To review and summarize what is known about cerebrovascular derangements during preeclampsia. RECENT FINDINGS: Preeclampsia is a devastating disorder of pregnancy with no known cure. Little is known about the pathophysiological mechanisms which lead to the symptoms of the disorder, particularly with regard to individual vascular beds such as the cerebral circulation. Studies suggest that the cerebrovascular dysfunction characteristic of the preeclampsia syndrome is characterized by alterations in cerebral blood flow autoregulation and opening of the blood-brain barrier. Mechanistic studies demonstrate that the same circulating factors implicated in the pathophysiology of other vascular beds may be operative in the cerebral circulation as well. However, significant knowledge gaps still exist, highlighting the need for more intense research in this field. Little is known about cerebrovascular dysfunction during preeclampsia, and detailed mechanistic studies are needed to identify the molecular pathways involved, the interactions thereof, and how those pathways lead to clinical disease.

Intraluminal pressure triggers myogenic response via activation of calcium spark and calcium-activated chloride channel in rat renal afferent arteriole.

Myogenic contraction of renal arterioles is an important regulatory mechanism for renal blood flow autoregulation. We have previously demonstrated that integrin-mediated mechanical force increases the occurrence of Ca2+ sparks in freshly isolated renal vascular smooth muscle cells (VSMCs). To further test whether the generation of Ca2+ sparks is a downstream signal of mechanotransduction in pressure-induced myogenic constriction, the relationship between Ca2+ sparks and transmural perfusion pressure was investigated in intact VSMCs of pressurized rat afferent arterioles. Spontaneous Ca2+ sparks were found in VSMCs when afferent arterioles were perfused at 80 mmHg. The spark frequency was significantly increased when perfusion pressure was increased to 120 mmHg. A similar increase of spark frequency was also observed in arterioles stimulated with ß1-integrin-activating antibody. Moreover, spark frequency was significantly higher in arterioles of spontaneous hypertensive rats at 80 and 120 mmHg. Spontaneous membrane current recorded using whole cell perforated patch in renal VSMCs showed predominant activity of spontaneous transient inward currents instead of spontaneous transient outward currents when holding potential was set close to physiological resting membrane potential. Real-time PCR and immunohistochemistry confirmed the expression of Ca2+-activated Cl- channel (ClCa) TMEM16A in renal VSMCs. Inhibition of TMEM16A with T16Ainh-A01 impaired the pressure-induced myogenic contraction in perfused afferent arterioles. Our study, for the first time to our knowledge, detected Ca2+ sparks in VSMCs of intact afferent arterioles, and their frequencies were positively modulated by the perfusion pressure. Our results suggest that Ca2+ sparks may couple to ClCa channels and trigger pressure-induced myogenic constriction via membrane depolarization.

A dynamic computational network model for the role of nitric oxide and the myogenic response in microvascular flow regulation.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.