Vascular Sympathetic Innervation Research Articles

Effect of sarpogrelate treatment on 5-HT modulation of vascular sympathetic innervation and platelet activity in diabetic rats

This study aimed to investigate whether the 5-HT2 receptor blockade alters the 5-HT effect on vascular sympathetic neurotransmission and platelet activation in type 1 diabetes. 28-day diabetes was obtained by alloxan (150 mg/kg; s.c.) in male Wistar rats, administering sarpogrelate (5-HT2 blocker; 30 mg/kg/day; p.o.) for 14 days. Blood glucose and body weight were monitored for 28 days. After 4 weeks of diabetes induction, food and drink intake, urine, plasma-platelet 5-HT, and platelet activation were determined in normoglycemic, non-treated diabetic and sarpogrelate-treated diabetic rats. Another set of diabetic rats were pithed to run the vascular sympathetic stimulation or exogenous noradrenaline administration, examining the induced vasoconstrictor responses. Sarpogrelate treatment significantly reduced drink intake and urine, whereas BW gain, hyperglycemia, and food intake were not modified in diabetic rats. The platelet activation and plasma 5-HT concentration were decreased (increasing the stored 5-HT platelet) by 5-HT2 blockade in diabetic animals. The sympathetic-induced vasoconstrictions were higher in non-treated than in sarpogrelate-treated diabetic rats. 5-HT inhibited these vasopressor responses, reproduced exclusively by the 5-HT1/5/7 receptor agonist, 5-CT. The 5-CT-produced inhibition was partly reversed by 5-HT1D or 5-HT7 antagonists (LY310762 or SB-258719, respectively), and totally annulled by the mixture of LY310762+SB‐258719. Noradrenaline-caused vasoconstrictions were also decreased by 5-CT. In conclusion, our results reveal that 14-day sarpogrelate treatment improves polydipsia and polyuria, reduces platelet hyperactivation, plasma 5-HT and the vascular sympathetic tone, and changes 5-HT receptors inhibiting noradrenergic drive in diabetic rats: pre and/or postjunctional 5-HT1D/7 are involved in the sympatho-inhibition.

Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats.

Nitric oxide (NO) has been shown to stimulate differentiation and increase the survival of ganglionic sympathetic neurons. The proportion of neuronal NOS-immunoreactive sympathetic preganglionic neurons is particularly high in newborn rats and decreases with maturation. However, the role of NO in the development of vascular sympathetic innervation has never been studied before. We tested the hypothesis that intrauterine NO deficiency weakened the development of vascular sympathetic innervation and thereby changed the contractility of peripheral arteries and blood pressure level in two-week-old offspring. Pregnant rats consumed NOS inhibitor L-NAME (250 mg/L in drinking water) from gestational day 10 until delivery. Pups in the L-NAME group had a reduced body weight and blood level of NO metabolites at 1–2 postnatal days. Saphenous arteries from two-week-old L-NAME offspring demonstrated a lower density of sympathetic innervation, a smaller inner diameter, reduced maximal active force and decreased α-actin/β-actin mRNA expression ratio compared to the controls. Importantly, pups in the L-NAME group exhibited decreased blood pressure levels before, but not after, ganglionic blockade with chlorisondamine. In conclusion, intrauterine L-NAME exposure is followed by the impaired development of the sympathetic nervous system in early postnatal life, which is accompanied by the structural and functional remodeling of arterial blood vessels.

Which sympathoadrenal abnormalities of adult spontaneously hypertensive rats can be traced to a prehypertensive stage?

Alterations of sympathoadrenal and sympathoneural systems have been suggested to be involved in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). To evaluate the ontogenetic changes of these systems, mRNA and protein expressions of catecholaminergic system genes were measured in adrenal glands and sympathetic ganglia, and the catecholamine levels were determined in adrenal glands, sympathetic ganglia and plasma of prehypertensive (4-week-old) and hypertensive (24-week-old) SHR. Vascular sympathetic innervation was visualized in the femoral artery by glyoxylic acid. In the adrenal glands of prehypertensive SHR, the expression of catecholamine biosynthetic enzymes Ddc, Dbh and Pnmt was lower than in aged-matched Wistar-Kyoto rats. In contrast, the adrenal content of dopamine, noradrenaline and adrenaline was higher in prehypertensive SHR (141%, 123% and 120% of Wistar-Kyoto rats, respectively, p < 0.01). In the adrenal glands of adult SHR, the expression of catecholamine biosynthetic enzymes Th, Ddc, Dbh and Pnmt was decreased along the amounts of dopamine and noradrenaline (50% and 38%, respectively, p < 0.001). The expression levels of Ddc and Dbh enzymes were also downregulated in the sympathetic ganglia of both prehypertensive and adult SHR. At both ages, the density of sympathetic innervation was twofold higher in SHR compared to Wistar-Kyoto rats (p < 0.001). In conclusion, adrenal catecholamine content was increased in prehypertensive SHR, whereas it was reduced in SHR with established hypertension. Surprisingly, downregulation of catecholamine biosynthetic enzymes was observed in both the adrenal medulla and sympathetic ganglia of SHR at both ages. Thus, this downregulation might be a compensatory mechanism that counteracts the vascular sympathetic hyperinnervation seen in SHR of both ages.

Relationship between Vascular Resistance and Sympathetic Nerve Fiber Density in Arterial Vessels in Children With Sleep Disordered Breathing.

BackgroundSleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early‐onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans.Methods and ResultsThirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow‐mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral (r=0.63; P<0.05) and a lower Neuronal Pupillary Index (r=−0.71, P<0.01), as well as a slower mean pupillary constriction velocity (mean, r=−0.64; P<0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity (r=−0.77; P<0.01) and higher platelet aggregation to collagen antigen (r=0.64; P<0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores (P<0.05; P<0.01, respectively).ConclusionsThese results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing.

Eph/ephrin interactions modulate vascular sympathetic innervation

Ephs and ephrins are membrane-bound proteins that interact to modulate axon growth and neuronal function. We tested the hypothesis that eph/ephrin interactions affected the growth and function of vascular sympathetic innervation. Using RT-PCR analyses, we detected both classes of ephs (A and B) and both classes of ephrins (A and B) in sympathetic ganglia from neonatal and adult rats. Both classes of ephs (A and B) and both classes of ephrins (A and B) bound to the cell bodies and neurites of dissociated postganglionic sympathetic neurons. Messenger RNAs encoding for both classes of ephs (A and B) and both classes of ephrins (A and B) were also detected in sympathetically innervated arteries from neonatal and adult rats. These data suggest that ephrins/ephs on nerve fibers of postganglionic sympathetic neurons could interact with ephs/ephrins on cells in innervated arteries. We found that ephA4 reduced reinnervation of denervated femoral arteries. Reinnervation in the presence of ephA4-Fc (38.9 ± 6.6%) was significantly less than that in the presence of IgG–Fc (62 ± 10%; n = 5; p < 0.05; one-tailed unpaired t-test). These data indicate that eph/ephrin interactions modulated the growth of vascular sympathetic innervation. We also found that ephA4 increased basal release of norepinephrine from nerve terminals of isolated tail arteries. These data indicate that eph/ephrin interactions affect the growth and function of vascular sympathetic innervation.

The p75 neurotrophin receptor, semaphorins, and sympathetic traffic in the heart

the sympathetic and parasympathetic branches of the autonomic nervous system control cardiac function through the coordinated activity generated by neurons within the intracardiac autonomic ganglia and central nervous system (3). Activation of the sympathetic efferent projections to the heart increases heart rate, modifies the pattern and conduction velocity of the impulse through the heart, and augments both atrial and ventricular contractility while hastening myocardial relaxation. In the vasculature, the sympathetic nervous system (SNS) reduces venous capacitance and constricts resistance vessels, increasing blood pressure. Conversely, the parasympathetic nervous system (PSNS) decreases heart rate and cardiac impulse conduction. More recent evidence has suggested that the PSNS may also affect ventricular function, indirectly by countering β-adrenergic action or directly via inhibition of L-type Ca2+ channels (34). A transient imbalance between these two branches can lead to increased heart rate and blood pressure when cardiac output is increased. When subnormal cardiac PSNS activity concomitant with sympathetic hyperactivation persists, such as after myocardial infarction, this disequilibrium may increase the risk for cardiac adverse events, including arrhythmias, hypertension, cardiac hypertrophy, and, ultimately, heart failure. This condition is called “autonomic neural remodeling” and can greatly contribute to the induction of ventricular fibrillation, thus increasing the patient's susceptibility to sudden cardiac death (41, 47). It is plausible that neurotrophic factors, target organ-secreted proteins essential for the development and differentiation of neurons, are involved in the remarkable neuroplasticity exhibited by the SNS in the adult life, including autonomic remodeling after infarction and/or in the onset and progression of congestive heart failure (17, 30, 32).

VEGF-A and Semaphorin3A: Modulators of vascular sympathetic innervation

Sympathetic nerve activity regulates blood pressure by altering peripheral vascular resistance. Variations in vascular sympathetic innervation suggest that vascular-derived cues promote selective innervation of particular vessels during development. As axons extend towards peripheral targets, they migrate along arterial networks following gradients of guidance cues. Collective ratios of these gradients may determine whether axons grow towards and innervate vessels or continue past non-innervated vessels towards peripheral targets. Utilizing directed neurite outgrowth in a three-dimensional (3D) co-culture, we observed increased axon growth from superior cervical ganglion explants (SCG) towards innervated compared to non-innervated vessels, mediated in part by vascular endothelial growth factor (VEGF-A) and Semaphorin3A (Sema3A) which both signal via neuropilin-1 (Nrp1). Exogenous VEGF-A, delivered by high-expressing VEGF-A-LacZ vessels or by rhVEGF-A/alginate spheres, increased sympathetic neurite outgrowth while exogenous rhSema3A/Fc decreased neurite outgrowth. VEGF-A expression is similar between the innervated and non-innervated vessels examined. Sema3A expression is higher in non-innervated vessels. Spatial gradients of Sema3A and VEGF-A may promote differential Nrp1 binding. Vessels expressing high levels of Sema3A favor Nrp1-PlexinA1 signaling, producing chemorepulsive cues limiting sympathetic neurite outgrowth and vascular innervation; while low Sema3A expressing vessels favor Nrp1-VEGFR2 signaling providing chemoattractive cues for sympathetic neurite outgrowth and vascular innervation.

VEGF promotes vascular sympathetic innervation

The sympathetic nervous system, via postganglionic innervation of blood vessels and the heart, is an important determinant of cardiovascular function. The mechanisms underlying sympathetic innervation of targets are not fully understood. This study tests the hypothesis that target-derived vascular endothelial growth factor (VEGF) promotes sympathetic innervation of blood vessels. Western blot and immunohistochemical analyses indicate that VEGF is produced by vascular cells in arteries and that VEGF receptors are expressed on sympathetic nerve fibers innervating arteries. In vitro, exogenously added VEGF and VEGF produced by vascular smooth muscle cells (VSMCs) in sympathetic neurovascular cocultures inhibited semaphorin 3A (Sema3A)-induced collapse of sympathetic growth cones. In the absence of Sema3A, VEGF and VSMCs also increased growth cone area. These effects were mediated via VEGF receptor 1. In vivo, the neutralization of VEGF inhibited the reinnervation of denervated femoral arteries. These data demonstrate that target-derived VEGF plays a previously unrecognized role in promoting the growth of sympathetic axons.

Determining the molecular mechanisms of vascular sympathetic innervation

Sympathetic nerves regulate blood pressure via peripheral vasoconstriction and redistribution of cardiac output. As some arteries are innervated while others are not, we tested the hypothesis that molecular cues expressed by vessels promote attraction and/or repulsion of sympathetic neurons. In CD1 mice, tyrosine hydroxylase staining shows sympathetic innervation of femoral arteries increases from 52 to 75% of adult innervation densities between birth and 2d postnatal (p&lt;0.01) and was not different from adult by 4d. Using qRT‐PCR, expression profiles of known candidate molecules between innervated femoral and non‐innervated carotid arteries included significant (p&lt;0.01) increases in carotid Sema3a (3X), femoral VEGF (3X) and Sema3f (2X). In addition, their cognate receptors neuropilin‐1, VEGFR2 and neuropilin‐2 are expressed in superior cervical ganglia (SCG). Suppression subtractive hybridization is being used to identify novel candidates. Further, in a 3D collagen gel, average neurite outgrowth from SCG explants towards the femoral is increased by 20% (p&lt;0.01) compared to carotid suggesting that chemorepulsion contributes to lack of carotid innervation. These findings provide evidence of differential expression of axon guidance molecules by innervated and non‐innervated vessels and present an model for investigating selective vascular innervation. R37 HL28373 to JAM, T32 GM07527.

Vascular‐derived VEGF: A determinant of vascular sympathetic innervation?

Vascular‐derived VEGF: A determinant of vascular sympathetic innervation?

Vascular-derived artemin: a determinant of vascular sympathetic innervation?

Vascular sympathetic innervation is an important determinant of blood pressure and blood flow. The mechanisms that determine vascular sympathetic innervation are not well understood. The present study tests the hypothesis that vascular-derived artemin promotes the development of sympathetic innervation to blood vessels by promoting sympathetic axon growth. RT-PCR and Western analyses indicate that artemin is expressed by cultured vascular smooth muscle and arteries, and artemin coreceptors, glial cell-derived neurotrophic factor family receptor alpha3 and ret, are expressed by postganglionic sympathetic neurons. The effects of artemin on axon growth were assessed on explants of neonatal rat sympathetic ganglia. In the presence, but not in the absence, of nerve growth factor, exogenous artemin stimulated neurite growth. Femoral arteries (FA) from adult rats contain artemin, and these arteries stimulated sympathetic neurite growth. Growth in the presence of FA was 92.2 +/- 11.9 mm, and that in the absence of FA was 26.3 +/- 5.4 mm (P < 0.05). FA stimulation of axon growth was reduced by an antibody that neutralized the activity of artemin (P < 0.05). These data indicate that artemin is expressed in arteries, and its receptors are expressed and functional in the postganglionic sympathetic neurons that innervate them. This suggests that artemin may be a determinant of vascular sympathetic innervation.

Regional differences in vascular sympathetic innervation are maintained in aging C57Bl/6 mice

Sympathetic innervation is integral to regional blood flow control. It is unknown whether regional differences in the density of sympathetic innervation change with aging. We investigated these relationships using male C57Bl/6 mice (‘Young’ = 3 mo, n=5; ‘Old’ = 20 mo, n=5). Carotid and femoral conduit arteries, feed arteries of the gracilis muscle, and second-order mesenteric arteries and veins were isolated, secured at in situ dimensions and immunolabeled for tyrosine hydroxylase. Total nerve length and surface area for the superficial half of each vessel segment (length = 400–700 μm) was quantified using 3-D mapping (Neurolucida) of fluorescent images (magnification, 886X; ~1 μm resolution) to calculate innervation density (total nerve length/total surface area; μm/μm2). Carotid arteries were devoid of labeling. In Young, mesenteric and femoral arteries were surrounded by dense nerve plexuses along the vessel and had the highest innervation densities (0.075 ± 0.002 and 0.079 ± 0.003, respectively). Innervation densities were ~40% lower (P < 0.05) for mesenteric veins (0.052 ± 0.002) and gracilis feed arteries (0.040 ± 0.002), with nerve fibers distributed sparsely along vessels. Old were not different from Young for any vessel. These findings demonstrate regional variation in the density of sympathetic innervation that is unaffected by aging (through 20 mo) in mice. We conclude that regional differences in vascular sympathetic innervation remain central to cardiovascular regulation during physical stress. (Support: R21 AG19347 and T32 GM07527)

Vascular endothelial growth factor/semaphorin/neuropilin interactions at sympathetic neurovascular junctions

Several lines of evidence suggest that vascular endothelial growth factor (VEGF) and semaphorin (sema) interact via neuropilin (npn) receptors to modulate axon growth. The present study tests the hypothesis that VEGF/sema/npn interactions modulate axon growth at sympathetic neurovascular junctions. RT-PCR and western analyses indicate that VEGF, sema and npn-1 are expressed at sympathetic neurovascular junctions (SNJ). Neutralization of VEGF (VEGF Ab) decreased outgrowth of axons from explanted sympathetic ganglia. Axon growth in the presence of VEGF Ab (248 + 68 mm) was less than that in the absence of antibody (830 + 201 mm; p = 0.05; unpaired t-test; n = 4). We have previously shown that inhibition of sema binding to npn-1 promotes growth of sympathetic axons towards neonatal carotid arteries. Time lapse video microscopy was used to visualize rapid responses to sema in living sympathetic axons. Sema 3A (200 ng/ml for 30 minutes) collapsed sympathetic axons grown in the absence (5 out of 6) but not in the presence of VSM (0 out of 5). These data indicate that VEGF, sema, and npn-1 are present and functional at SNJs. These data also suggest a novel interaction between VSM and sympathetic neurons that may modulate the actions of sema at SNJs. These data support our hypothesis that interactions between VEGF, sema, and npn-1 contribute to the development and/or maintenance of vascular sympathetic innervation. HL076774.

Vascular endothelial-derived semaphorin 3 inhibits sympathetic axon growth

Vascular sympathetic innervation is an important determinant of blood pressure and blood flow. The mechanisms that determine vascular sympathetic innervation are not well understood. Recent studies indicate that vascular endothelial cells (EC) express semaphorin 3A, a repulsive axon guidance cue. This suggests that EC would inhibit the growth of axons to blood vessels. The present study tests this hypothesis. RT-PCR and Western analyses confirmed that rat aortic vascular ECs expressed semaphorin 3A as well as other class 3 semaphorins (sema 3s). To determine the effects of EC-derived sema 3 on sympathetic axons, axon outgrowth was assessed in cultures of neonatal sympathetic ganglia grown for 72 h in the absence and presence of vascular EC. Nerve growth factor-induced axon growth in the presence of ECs was 50 +/- 4% (P < 0.05) of growth in the absence of ECs. ECs did not inhibit axon growth in the presence of an antibody that neutralized the activity of sema 3 (P > 0.05). RT-PCR and Western analyses also indicated that sema 3s were expressed in ECs of intact arteries. To assess the function of sema 3s in arteries, sympathetic ganglia were grown in the presence of arteries for 72 h, and the percentage of axons that grew toward the artery was determined: 44 +/- 4% of axons grew toward neonatal carotid arteries. Neutralization of sema 3s or removal of EC increased the percentage of axons that grew toward the artery (71 +/- 8% and 72 +/- 8%, respectively). These data indicate that vascular EC-derived sema 3s inhibit sympathetic axon growth and may thus be a determinant of vascular sympathetic innervation.

Sema3a is produced by brown adipocytes and its secretion is reduced following cold acclimation.

Heat production in brown adipose tissue (BAT) and brown adipocyte recruitment depend heavily on BAT vascular and parenchymal sympathetic and sensory innervation. The expression and distribution of Sema3a, a recently discovered chemorepellent neuronal factor active on both sympathetic and sensory peripheral nerves, were studied in interscapular rat BAT. In rats maintained in thermoneutral conditions, brown adipocytes produced both active isoforms of Sema3a and showed a distinct peripheral polarized immunostaining pattern. This suggests a role for Sema3a secreted by brown adipocytes in the guidance of axons toward their correct targets. In cold-acclimated rats, where parenchymal nerve density is higher, both the expression and the immunostaining of the two active isoforms were slightly but significantly reduced and the distinct staining pattern was not observed. These data suggest that the secretion of Sema3a is inhibited in the brown adipocytes of cold-acclimated rats. Thus, Sema3a could play a role in the plastic adjustment of BAT innervation observed in different conditions of functional demand.

Prenatal cocaine exposure affects the development of aortic adrenergic innervation and contractile responses

This study examines the effects of prenatal cocaine administration on the development of vascular sympathetic innervation and contractile responsiveness. Rabbits received cocaine (4 mg/kg, iv, bid) or saline during gestational days 8 to 29. Aortas were obtained on postnatal days 10, 20, 30 and 50. Vascular smooth muscle responsiveness was assessed by measuring aortic contractile responses to norepinephrine (NE) and to other vasoconstrictors. Vascular adrenergic innervation was evaluated by measuring desipramine sensitive [ 3H]-NE uptake into aortic ring segments and aortic NE content. [ 3H]-NE uptake and NE content were reduced at postnatal days 10 and 20 in the rabbits exposed prenatally to cocaine. Differences were not observed at postnatal days 30 or 50. The contractile response to NE was reduced in rabbits exposed to cocaine prenatally. Maximal response and potency were decreased at postnatal day 10 and potency was still decreased at day 20, but not at the older ages. Contractile responses to serotonin (5-HT) and angiotensin II (AII) were not affected by prenatal cocaine exposure. These results suggest that prenatal cocaine exposure delays the development of aortic adrenergic innervation and alpha adrenoceptor responsiveness.

Adrenergic innervation of blood vessels in Dahl rats with salt hypertension.

The adrenergic innervation of major arteries and veins was examined in Dahl salt-sensitive (DS) and salt-resistant (DR) rats using a histochemical fluorescent technique to detect the intraneuronal catecholamine content. Under the conditions of low salt intake the density of adrenergic plexus tended to be higher in DR than in DS rats. A decrease of catecholamine content with a subsequent reduction in the density of visible adrenergic plexus was observed in mesenteric and renal but not in femoral vascular beds of salt hypertensive DS rats. The adrenergic innervation was more altered in veins than in respective arteries. Pronounced alterations of vascular sympathetic innervation induced by high salt intake in DS rats contrasted with negligible changes occurring in DR animals. Observed changes of adrenergic innervation in particular vascular beds of salt hypertensive DS rats could reflect the enhanced catecholamine turnover and sympathetic hyperactivity which is important for the pathogenesis and/or maintenance of salt hypertension in Dahl salt-sensitive rats.

‘Neuropeptide tyrosine’ (NPY) is co-stored with noradrenaline in vascular but not in parenchymal sympathetic nerves of brown adipose tissue

By using immunohistochemistry it is shown that both the parenchymal and vascular sympathetic innervation in the interscapular depot of brown adipose tissue in the rat contain the catecholamine-synthesizing enzyme tyrosine-hydroxylase (TH). In contrast, ‘neuropeptide tyrosine’ (NPY) is selectively present in the vascular sympathetic nerves of the tissue—but not in nerves around brown fat cells. This is consistent with the presence of two populations of neurons (containing either TH alone or TH plus NPY) in the stellate ganglion, which is the probable origin of the sympathetic nerves in the interscapular brown adipose tissue. Furthermore, the perivascular NPY-positive nerves in the brown adipose tissue disappeared after 6-hydroxydopamine treatment, demonstrating their noradrenergic nature. Taken together, these findings suggest that sympathetic nerves to blood vessels and brown fat cells represent two separate subpopulations of autonomic neurons.

Sympathetic activity, lipids accumulation, and arterial wall morphology in rabbits at high altitude.

The purpose of this study was to investigate the effect of increased sympathetic nervous activity on arterial wall viability as reflected by its response to elevated plasma lipids. Our previous finding that vascular wall viability was reduced by low sympathetic nervous activity indicated that chronically enhanced sympathetic activity should have the opposite effect. In this study rabbits were divided into two groups, both of which received 1% cholesterol in the diet. One group was born and raised at high altitude to induce chronic activation of sympathetic activity, and the other was raised at sea level. Aorta of high-altitude rabbits exhibited significantly less lipid accumulation than aortas of sea-level rabbits. This difference in lipid accumulation was accompanied by elevated norepinephrine turnover and decreased sensitivity to exogenous norepinephrine of high-altitude rabbit arteries. Vascular smooth muscle cells of high-altitude rabbits demonstrated striated increased relative volume density of mitochondria and decreased nucleocytoplasmic ratio, reflecting lower mitotic rate. These results are suggestive that enhanced chronic activity of vascular sympathetic innervation protects smooth muscle from lipid accumulation and exerts a positive effect on vascular viability.