Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis.

Alcohol abuse has a negative impact on human health; however, epidemiological studies show that moderate consumption of ethanol (EtOH) reduces the risk of coronary heart disease, sudden cardiac death, and ischemic stroke. The mechanisms for these reductions in cardiovascular disease are not well established. Using cultured coronary artery vascular smooth muscle cells, we found that moderate levels of EtOH (10 and 20 mM) caused dose-related increases in both vascular endothelial growth factor (VEGF) mRNA (Northern blot) expression (1.9- and 2.6-fold) and VEGF protein (ELISA) expression (19 and 68%) compared with control (P < 0.05). EtOH at 0.25 g. kg(-1). day(-1) (7 days) increased VEGF mRNA expression by 1.48-fold over control, and increased vessel length density from 3.9 +/- 0.7 (control) to 6.0 +/- 0.3 mm/mm(2) (P < 0.05) in chick chorioallantoic membrane (CAM). We conclude that moderate levels of ethanol can induce VEGF expression and stimulate angiogenesis in chick CAM. Therefore, the results provide a theoretical basis for speculating that the cardiovascular-protective effects of moderate alcohol consumption may be partly mediated through VEGF-induced angiogenesis.

Inhibition of adenosine kinase induces expression of VEGF mRNA and protein in myocardial myoblasts.

We tested whether increased endogenous adenosine produced by the adenosine kinase inhibitor GP-515 (Metabasis Therapeutics) can induce vascular endothelial growth factor (VEGF) expression in cultured rat myocardial myoblasts (RMMs). RMMs were cultured for 18 h in the absence (control) and presence of GP-515, adenosine (Ado), adenosine deaminase (ADA), or GP-515 + ADA. GP-515 (0.2-200 microM) caused a dose-related increase in VEGF protein expression (1.99-2.84 ng/mg total cell protein); control VEGF was 1.84 +/- 0.05 ng/mg. GP-515 at 2 and 20 microM also increased VEGF mRNA by 1.67- and 1. 82-fold, respectively. ADA (10 U/ml) decreased baseline VEGF protein levels by 60% and completely blocked GP-515 induction of VEGF. Ado (20 microM) and GP-515 (20 microM) caused a 59 and 39% increase in VEGF protein expression and a 98 and 33% increase in human umbilical vein endothelial cell proliferation, respectively, after 24 h of exposure. GP-515 (20 microM) had no effect on VEGF protein expression during severe hypoxia (1% O(2)) but increased VEGF by an additional 27% during mild hypoxia (10% O(2)). These results indicate that raising endogenous levels of Ado through inhibition of adenosine kinase can increase the expression of VEGF and stimulate endothelial cell proliferation during normoxic and hypoxic conditions.

Adenosine upregulates VEGF expression in cultured myocardial vascular smooth muscle cells.

We tested whether adenosine has differential effects on vascular endothelial growth factor (VEGF) expression under normoxic and hypoxic conditions, and whether A(1) or A(2) receptors (A(1)R; A(2)R) mediate these effects. Myocardial vascular smooth muscle cells (MVSMCs) from dog coronary artery were exposed to hypoxia (1% O(2)) or normoxia (20% O(2)) in the absence and presence of adenosine agonists or antagonists for 18 h. VEGF protein levels were measured in media with ELISA. VEGF mRNA expression was determined with Northern blot analysis. Under normoxic conditions, the adenosine A(1)R agonists, N(6)-cyclopentyladenosine and R(-)-N(6)-(2-phenylisopropyl)adenosine did not increase VEGF protein levels at A(1)R stimulatory concentrations. However, adenosine (5 microM) and the adenosine A(2)R agonist N(6)-[2-(3, 5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyl adenosine (DPMA; 100 nM) increased VEGF protein levels by 51 and 132% and increased VEGF mRNA expression by 44 and 90%, respectively, in cultured MVSMCs under normoxic conditions. Hypoxia caused an approximately fourfold increase in VEGF protein and mRNA expression, which could not be augmented with exogenous adenosine, A(2)R agonist (DPMA), or A(1)R agonist [1,3-diethyl-8-phenylxanthine (DPX)]. The A(2)R antagonist 8-(3-chlorostyryl)-caffeine completely blocked adenosine-induced VEGF protein and mRNA expression and decreased baseline VEGF protein levels by up to approximately 60% under normoxic conditions but only by approximately 25% under hypoxic conditions. The A(1)R antagonist DPX had no effect. These results are consistent with the hypothesis that 1) adenosine increases VEGF protein and mRNA expression by way of A(2)R. 2) Adenosine plays a major role as an autocrine factor regulating VEGF expression during normoxic conditions but has a relatively minor role during hypoxic conditions. 3) Endogenous adenosine can account for the majority of basal VEGF secretion by MVSMCs under normoxic conditions and could therefore be a maintenance factor for the vasculature.

Sodium induces hypertrophy of cultured myocardial myoblasts and vascular smooth muscle cells.

The mechanisms of sodium-induced myocardial hypertrophy and vascular hypertrophy are poorly understood. We tested the hypothesis that a high sodium concentration can directly induce cellular hypertrophy. Neonatal rat myocardial myoblasts (MMbs) and vascular smooth muscle cells (VSMCs) were cultured in a 50:50 mixture of DMEM and M199 supplemented with 10% fetal bovine serum. When the monolayers reached approximately 80% confluence, normal sodium medium (146 mmol/L) was replaced with high sodium media (152 mmol/L, 160 mmol/L, and 182 mmol/L) for up to 5 days. Increasing sodium from a baseline concentration of 146 mmol/L to the higher concentrations for 5 days caused dose-related increases in cell mean diameter, cell volume, and cellular protein content in both MMbs and VSMCs. Increasing the sodium concentration by only 4% (from 146 mmol/L to 152 mmol/L) caused the following respective changes in MMbs and VSMCs: 8.5% and 8.7% increase in cell mean diameter, 27.6% and 27.0% increase in cell volume, and 55.7% and 46.7% increase in cellular protein content. The rate of protein synthesis, expressed as [3H]leucine incorporation, increased by 87% and 99% in MMbs after exposure to 152 mmol/L and 160 mmol/L sodium, respectively, compared with the 146-mmol/L sodium control group. Exposure of MMbs to medium with a sodium concentration of 10% above normal, ie, 160 mmol/L, caused a significant decrease (range, 26% to 44%) in the rate of protein degradation at multiple time points over a 48-hour period compared with normal sodium control cells. The increase in cellular protein content caused by 160 mmol/L sodium returned to normal within 3 days after MMbs were returned to a normal sodium medium. These findings support the hypothesis that sodium has a direct effect to induce cellular hypertrophy and may therefore be an important determinant in causing myocardial and/or vascular hypertrophy in subjects with increased sodium concentration in the extracellular fluid.

Hypoxia-induced expression of VEGF is reversible in myocardial vascular smooth muscle cells.

We determined whether hypoxia-induced expression of vascular endothelial growth factor (VEGF) can be reversed by a normoxic environment. Dog myocardial vascular smooth muscle cells (MVSMCs) were exposed to hypoxia (1% O2) for 24 h and then returned to normoxia (20% O2). VEGF protein levels increased by more than fivefold after 24 h of hypoxia and returned to baseline within 24 h of the return of the cells to normoxia. Northern blot analysis showed that hypoxia caused a 5.5-fold increase in VEGF mRNA, and, again, the expression was reversed after reinstitution of normoxia. Additional measurements showed that basic fibroblast growth factor and platelet-derived growth factor protein levels were not induced by hypoxia and that hypoxia caused a fourfold decrease in transforming growth factor-beta 1 protein levels. Hypoxia conditioned media from MVSMCs caused human umbilical vein endothelial cells to increase [3H]thymidine incorporation by twofold, an effect that was blocked in a dose-dependent manner by anti-human VEGF antibody. The hypoxia conditioned media had no effect on MVSMC proliferation. These findings suggest that VEGF expression can be bidirectionally controlled by tissue oxygenation, and thus support the hypothesis that VEGF is a physiological regulator of angiogenesis.

Capillary-to-fiber surface ratio in rat fast-twitch hindlimb muscles after chronic electrical stimulation.

We examined the relative plasticity of capillaries and fiber mitochondria in rat fast-twitch hindlimb muscles in response to chronic electrical stimulation. Specifically we addressed whether the size of the capillary-fiber interface increases in proportion to fiber mitochondrial volume, inasmuch as fiber aerobic capacity increases severalfold with chronic stimulation. Tibialis anterior and extensor digitorum longus muscles of six rats [367 +/- 17 (SD) g body wt] were stimulated (10 Hz, 8 h/day, 7 days/wk) for 28 consecutive days. Subsequently they were perfusion fixed in situ and stimulated, and contralateral control samples from the midbelly were processed for electron microscopy and morphometry. Capillary length density, capillary-to-fiber ratio, and fiber mitochondrial volume density increased two- to threefold in stimulated muscles, with no change in fiber or capillary diameter. Capillary-to-fiber surface area ratio per fiber unit mitochondrial volume was unchanged in stimulated muscles compared with contralateral controls, indicating a proportional increase in the size of the capillary-fiber interface and fiber mitochondrial volume in the muscles after chronic electrical stimulation.

VEGF gene expression is upregulated in electrically stimulated rat skeletal muscle.

Vascular endothelial growth factor (VEGF; also called vascular permeability factor) is a secreted mitogen with distinct target cell specificity for vascular endothelial cells. Hypoxia upregulates VEGF expression, making it a likely mediator of the angiogenesis that occurs in poorly perfused tissues. The purpose of this study was to determine whether VEGF gene expression is upregulated in chronically stimulated skeletal muscles, where hypoxia is thought to trigger the growth of blood vessels. The right anterior tibialis and extensor digitorum longus muscles of 12 rats were stimulated electrically (10 Hz, 300 microseconds pulses) for up to 21 days by way of the peroneal motor nerve. The contralateral muscles served as control. Northern analysis showed that VEGF mRNA levels increased by approximately sixfold after 4 days of stimulation and then decreased gradually over the next several days. VEGF mRNA levels were still elevated by two- to threefold after 21 days of stimulation. Higher VEGF mRNA levels in the early stages of muscle stimulation and gradually decreasing levels in later stages are consistent with a metabolic hypothesis in which tissue oxygenation controls VEGF expression. These studies support the hypothesis that VEGF has a physiological role in promoting angiogenesis in stimulated skeletal muscle.

Advantages of continuous measurement of cardiac output 24 h a day.

To test the hypothesis that continuous measurement of cardiac output 24 h a day would provide a better day-by-day reproducibility of the daily average cardiac output than acute measurements, we developed a computer-assisted method to monitor cardiac output continuously using an electromagnetic flow transducer. Because the diastolic aortic flow, which is used as a zero-flow reference, can drift significantly with electromagnetic flow probes, automatic tracking of the diastolic flow baseline was considered essential for long-term measurements. To accomplish this, the analog pulsatile flow signal was digitally converted and processed by an IBM PC to correct for signal drift on a beat-per-beat basis. Using this computerized system in 19 chronically instrumented dogs, we compared the values of cardiac output during 5 consecutive control days, measured either for 20 h each day (allowed 4 h for special care) or for 30 min in the morning when the trained dogs were required to lie quietly in their cages. The results show that the coefficient of variation of the five daily averages in cardiac output for each individual dog was three times smaller when cardiac output was measured 20 h each day (2.9 +/- 0.3 vs. 9.7 +/- 1.0%). Whole-day coefficients of variation were also smaller for mean arterial pressure, heart rate, stroke volume, and total peripheral resistance. Because of this greater day-by-day reproducibility, continuous monitoring of cardiac output is likely to be more sensitive to small changes in cardiac output induced by experimental protocols.

Long-term electrical stimulation of rabbit skeletal muscle increases growth of paired arteries and veins.

We tested whether chronic stimulation of skeletal muscle can increase the growth of paired arteries and veins in rabbit extensor digitorum longus muscle (EDL). The right EDL of female New Zealand White rabbits was stimulated via the common peroneal nerve at 10 Hz using 300 microseconds square waves at 3-4 V. Two-hour periods of stimulation was alternated with 4-h periods of rest, 7 days/wk for approximately 60 days. The left EDL served as control. The hindlimb vascular system was maximally dilated and perfuse-fixed with 3% glutaraldehyde and 2% paraformaldehyde at arterial and venous pressures of 80-100 and 15-20 mmHg, respectively. Muscles were postfixed in OsO4 and embedded in EPOX 812 resin. One millimeter-thick transverse sections were cut at uniform locations through the entire breadth of the muscle and analyzed using videomicroscopy along with computerized morphometric and stereological techniques. All paired arteries and veins on each full muscle section were analyzed. Chronic muscle stimulation caused the wall volume of paired arteries and veins to increase by an average of approximately twofold and the lumen volume to increase by an average of approximately threefold compared with the contralateral muscles. The wall-to-lumen area ratio of the arteries and veins was not affected. Muscle stimulation also caused the numerical density of arteries having a diameter > 100 microns to increase by approximately fourfold and the density of veins having a perimeter > 500 microns to increase by approximately 10-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Miniaturized electrical stimulator with controllable duty cycles.

A stimulator with adjustable duty cycles is described for chronic electrical stimulation of skeletal muscles by way of a motor nerve. The stimulator is unique in that it can stimulate a muscle or group of muscles for 2-h intervals that alternate with variable periods of rest (2, 4, 6, 8, or 10 h). A given duty cycle is selected with a rotary switch at the beginning of an experiment and will continue automatically, without human intervention, for the duration of the experiment. Other features include an adjustable voltage output, a stimulation indicator light-emitting diode (LED), and a low-battery indicator LED. The stimulator is powered by two 9-V batteries or can be used with a bench-top power supply. The stimulation frequency (10 Hz) and pulse width (300 microseconds) are fixed in our design but can be changed to other values by substituting two of the resistors and one capacitor in accordance with simple formulas. We have used the stimulator in rat and rabbit experiments to stimulate the anterior tibialis and extensor digitorum longus muscles for up to 60 days. The timing and output of the stimulator were found to be stable and accurate over the entire 60-day period. The stimulator and batteries were carried in a jacket worn by the rabbits. In the rat experiments, the stimulator was used in a remote fashion with the electrical leads connected to the animals by way of a tethering system. In both animals, the electrodes were implanted adjacent to the common peroneal nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

A stereological method for estimating length density of the arterial vascular system.

We developed a stereological method for quantitating length density (Lv; vessel length per unit reference volume) of the arterial system. Accurate estimation of Lv for a sparse system of blood vessels in a three-dimensional specimen requires information on individual vessel orientation. The method we present extracts the necessary information on vessel orientation from profile geometry. Major and minor diameters of elliptical profiles of sectioned tubular structures are used to calculate Lv. The method does not require special sectioning alignment and does not assume a prior distribution of blood vessels; however, the method does assume that arteries are cylindrical. A physical model consisting of boiled spaghetti mixed with agar in a cylinder was used to test the stereological method. Measurements of over 1,000 elliptical profiles in 5 separate trials have demonstrated that the method can accurately estimate Lv with < 5% error even when tortuosity is high, i.e., when anisotrophy coefficient is 1.55. This method may facilitate a better understanding of the mechanisms of artery growth by making it possible to quantify linear growth of the arterial system.

Effect of skin concavity on subcutaneous tissue fluid pressure.

We tested the hypothesis that mechanical factors associated, with a skin concavity can cause the local tissue fluid pressure to become more negative. Perforated Teflon collars, 26 mm in diameter and having various heights (5, 10, 13, and 16 mm), were implanted into the fascial plane of the inguinal and abdominal areas of six sheep. After several weeks, visible signs of edema were no longer apparent, and the skin formed a concavity within the center of each collar. The depth of each concavity was measured using an electronic micrometer, and the tissue fluid pressure beneath the concavity was measured using a needle method. Over the entire range of collar heights, the average depth of the concavities ranged from 1.1 to 4.7 mm in the abdominal tissues and from 1.8 to 5.5 mm in the inguinal tissues. The respective values of tissue fluid pressure averaged -4.6 to -13.0 and -5.7 to -12.8 mmHg. The results therefore indicate that implanting deeper collars leads to the formation of deeper concavities in the skin and also to greater negativity in the free tissue fluid pressure beneath the skin. Linear regression extrapolation to a collar height of 0 mm corresponded to a tissue fluid pressure of -1.0 mmHg in the abdominal tissue and -2.4 mmHg in the inguinal tissues. A model based on excessive pumping of the lymphatic system in the vicinity of a concavity is provided to explain this newly described phenomenon. We conclude that mechanical factors associated with the formation of a skin concavity cause or permit the tissue fluid pressure to reach levels of negativity far greater than those that exist in the absence of a concavity.

Morphometric measurements of chorioallantoic membrane vascularity: effects of hypoxia and hyperoxia.

We studied the effects of hypoxia and hyperoxia on the angiogenesis process in the chick embryo chorioallantoic membrane (CAM) using four different morphometric measurements of vascularity. Chick eggs were incubated in various oxygen atmospheres (12, 16, 21, 45, or 70% oxygen) beginning on the 7th day of development, and vascularity was measured on the 14th day. Measurements of vascularity included vessel endpoint density (VED), length density, fractional image area, and a vascular density index. All measurements were made on blood vessels in randomly selected areas of CAM using a computerized image analysis system. An opaque colloidal carbon-albumin perfusate was used as a vascular marker. All four measurements showed that vascularity of CAM was inversely related to the oxygen tension to which the embryos were subjected. The VED, an estimate of total number of pre- and postcapillary vessels, exhibited the greatest degree of change, but overall changes in vascularity were modest. Prolonged exposure to a 12% oxygen atmosphere increased VED by approximately 16%, whereas 70% oxygen decreased VED by approximately 19% compared with room air control groups. We also studied the normal growth of CAM vasculature from days 8 to 18 of development. In these studies, the values of VED increased progressively throughout the entire period of development, whereas the other measurements of vascularity reached maximum values by the 14th day. We conclude that hypoxia stimulates angiogenesis in the CAM in a dose-related manner, hyperoxia inhibits CAM angiogenesis in a dose-related manner, and VED provides a sensitive estimate of vascularity in chick CAM throughout its development.

Growth regulation of the vascular system: evidence for a metabolic hypothesis.

Prolonged imbalances between the perfusion capabilities of the blood vessels and the metabolic requirements of the tissue cells often lead to modification of the vasculature to satisfy the tissue needs. This homeostatic response appears to be bidirectional, since the vascularity of a tissue can increase or decrease in parallel with primary changes in metabolic rate. The factors that mediate the responses are not well understood, but oxygen has been implicated as a major control element, since vessel growth increases during hypoxic conditions and decreases during hyperoxic conditions. The following feedback control hypothesis may apply to many different physiological situations. Decreased oxygenation causes the tissues to become hypoxic, and this initiates a variety of signals that lead to the growth of blood vessels. The increase in vascularity promotes oxygen delivery to the tissue cells by decreasing diffusion distances, increasing capillary surface area, and increasing the maximum rate of blood flow. When the tissues receive adequate amounts of oxygen even during periods of peak activity, the intermediate effectors return to normal levels, and this negative signal, in turn, stops the further development of the vasculature. Although the effector mechanisms of the hypoxic stimulus are still being investigated, adenosine, which is produced in hypoxic tissues, appears to mediate hypoxia-induced increases in vascularity in some instances. Roles for fibroblast growth factor as well as mechanical factors associated with vasodilation and increased blood flow are postulated. Although blood vessel growth is a multifactorial process, a major influence in its regulation appears to be metabolic need. If this view is correct, it may be found that many of the quantitatively significant factors that control growth in a given vasculature are themselves modulated or controlled by metabolic signals reflecting the nutritional status of the tissues which that vasculature supplies.

Regulation of cardiac output during aldosterone-induced hypertension.

The classical haemodynamic transients of volume-loading hypertension have been difficult to demonstrate in aldosterone-induced hypertension. Because recent studies have shown that continuous whole-day measurements of cardiac output are superior to short-term recordings, we studied the transient haemodynamic effects of aldosterone-induced hypertension while monitoring arterial pressure and cardiac output (electromagnetic flow probe) continuously for 20 h a day. In six dogs maintained on a fixed sodium intake of 150 mmol/day, we infused aldosterone (12 micrograms/kg per day, intravenously) for 10 days. The aldosterone induced a progressive increase in mean arterial pressure, from a control value of 88 +/- 1 to 107 +/- 2 mmHg. Cardiac output increased progressively, reaching a peak average value on the 4th day of infusion of +14 +/- 5% above control, and remained slightly elevated throughout the infusion period. Total peripheral resistance increased slowly to a value averaging +13 +/- 4% above control. Therefore, our experiments show that aldosterone induces a primary increase in cardiac output followed by a secondary vasoconstriction, which is consistent with the classical transient haemodynamic effects of volume-loading hypertension.

Reflex modulation of lymphatic pumping in sheep.

Lymphatic pumping activity was examined in halothane-anesthetized sheep. A doubly cannulated preparation of the mesenteric lymph duct was "isolated" from lymph input, other than that from a constant pressure reservoir of artificial lymph attached to its inflow cannula, but had its blood supply and innervation intact. A cerebral ischemic response, evoked by injection of 2 ml air into the common carotid artery, increased both mean arterial pressure and fluid propulsion by the lymphatic. The latter rose from a control value of 45 microliters/min to a peak of 74 microliters/min. When 10(-4) M phentolamine was introduced into the lymphatic lumen, there was a transient increase followed by a sustained fall in lymph pumping. Repetition of the air injection while phentolamine was present in the duct lumen produced no increase in lymph pumping. In adrenalectomized animals, resting lymph propulsion by the mesenteric duct was depressed, and the response to air injection was attenuated but remained significantly greater than control. These results suggest that reflex activation of the sympathetic nervous system can increase lymph propulsion and that this may be augmented by the release of circulating catecholamines.

A simulation support system for solving large physiological models on microcomputers.

Although physiological modeling and computer simulation have become useful research tools to test new scientific theories and to design and analyze laboratory experiments, developing a new model can be a tedious process because the investigator must often write very complex and specific routines for data input and output. To facilitate the design of new models (as well as the use of existing models), we have developed MODSIM, a FORTRAN-based simulation support system for the IBM PC computer than can accommodate very large dynamic models having up to several thousand equations. It provides the investigator with utilities for continuous on-line graphical and/or tabular output, as well as facilities for dynamic interaction with the model. The user must only supply a model as a list of mathematical equations written in FORTRAN, along with the initial values of the model variables and parameters. The model is precompiled, compiled, and then linked to the MODSIM utilities. Without further programming, the user can then solve the model, select variables for graphical output, and stop the model at any time to analyze the data or to change a parameter before resuming the simulation. This simulation system makes it very easy to develop new models that actively interact with the experimental research of the investigator.

Vascular development in chick embryos: a possible role for adenosine.

We studied the possible role of adenosine in the development of the vasculature using 217 chick embryos. Adenosine (2-32 mumol/day), inosine (16 mumol/day), dipyridamole (0.04-0.4 mumol/day), or aminophylline (400 and 800 micrograms/day) were administered twice each day into the air space on days 11-14. Control embryos received Ringer solution. Whole body vascularity was estimated on day 15 as the whole body structural vascular resistance (SVR), i.e., the hydraulic resistance of the maximally dilated vasculature. Adenosine decreased the SVR in a dose-related manner at the lower dosage amounts but caused a maximum decrease in SVR at the higher dosage amounts averaging 30% below the Ringer control values. Equimolar amounts of adenosine and inosine decreased the SVR by the same extent. Dipyridamole, which potentiates the biological effects of endogenous adenosine, also decreased the SVR in a dose-related manner to values averaging approximately 30% below control. When the effects of endogenous adenosine were blocked by aminophylline, the SVR increased in a dose-related manner to approximately 100% above control at the highest dosage amount. These results suggest that adenosine could have a physiological role in growth regulation of the vascular system in the chick embryo.

Effects of intermittent hypoxia on structural vascular adaptation in chick embryos.

We explored whether the blood vascular system of the chick embryo adapts its structure to meet the maximum or average oxygen needs of the tissue cells. Chick embryos were grown in continuous 12% oxygen, continuous 16% oxygen, and intermittent 12% oxygen in which the embryos were exposed to 12% oxygen for 4 h each day. Control groups were grown in room air. Measurements of structural vascular resistance (SVR), i.e., the resistance of the maximally dilated vasculature, were used to estimate the whole body vascularity of the 14- or 15-day-old embryos. Continuous exposure to 12% oxygen decreased SVR by 63.1 +/- 1.2 (SE) %, and intermittent exposure to 12% oxygen decreased SVR by 55.6 +/- 0.5% when compared with a 15-day-old normoxic control group. Based on studies with continuous exposure to different levels of low oxygen, it was predicted that exposure to 19.5% oxygen, the average concentration for the intermittent hypoxia group, would decrease SVR by 15.0 +/- 0.3%. These results indicate that intermittent hypoxia at 12% oxygen was approximately 90% as effective as continuous hypoxia at the same level in decreasing SVR and about four times more effective than 19.5% continuous oxygen. Therefore, the results support the hypothesis that the blood vascular system adapts its structure to meet almost entirely the maximum oxygen needs of the tissue cells.