Microcirculatory Network Research Articles

Effect of intravenous PDE-5 inhibitor Sildenafil on pulmonary microcirculation n

Objectives: Phosphodiesterase-5-inhibitor Sildenafil (PDE-5-INH) has been proposed for the treatment of pulmonary hypertension. However, effects on the microcirculatory network have never been observed up until today. It was the aim of our study to evaluate the effect of a PDE-5-INH on the pulmonary microcirculation in a big animal model.

54: Effects of PDE-5 inhibitor on pulmonary macro- and microcirculation

Phosphodiesterase-5 inhibitor (PDE-5 INH) Sildenafil has been proposed for the treatment of pulmonary hypertension because of its dilatative effect on the pulmonary vessels. However, effects on the pulmonary microcirculatory network have never been observed up until today. It was therefore the aim of our study to evaluate the effects of the PDE-5 INH on the pulmonary microcirculation in a big animal model.

Depression and cardiovascular disease: a reciprocal relationship

Until relatively recently, depression has been considered a purely “mental” disorder and therefore in the natural domain of psychologists and psychiatrists. However, recent epidemiological studies have revealed that aging, physical and psychological stress, chronic pain, several metabolic disorders such as insulin resistance and established diabetes, alcoholism, inflammatory conditions, and vascular disorders such as arterial hypertension all may be associated with depression. The present review examines some of these depression-associated factors and the mechanisms by which they might give rise to vascular disorders such as atherosclerosis, microcirculation endothelial dysfunction, and interstitial disturbances leading to organ damage. A number of disorders involving the circulation can lead progressively and insidiously to large artery rigidity, remodeling of peripheral arteries, and alterations of the microcirculation of large blood vessels. Perturbations in vasa vasorum blood flow may contribute to atherogenesis, in addition to the influence of numerous cellular events involved in inflammation (tumor necrosis factor α, interleukin 1 β, etc). Since Hans Selye first described the neuroendocrine cascade generated by experimentally induced stress half a century ago, phenomena such as the axonal release of neurotransmitters (including serotonin), accumulation of metabolites such as homocysteine, platelet-activating factor, and nitric oxide also have been implicated in the pathogenesis of depression. Moreover, vascular consequences of depression such as heart rate and pulse pressure variations may lead to endothelial dysfunction in critical microcirculation networks (cerebral, myocardial, and renal) and initiate physicochemical alterations in interstitial compartments adjacent to vital organs. The appropriate use of ambulatory monitoring of vascular parameters, such as heart rate and pulse pressure, and eventually, early identification of genetic and metabolic markers may prove helpful in the early detection of events preceding and predicting the clinical manifestations of depression.

An intravital microscopy study of radiation-induced changes in permeability and leukocyte–endothelial cell interactions in the microvessels of the rat pia mater and cremaster muscle

Using intravital microscopy and a closed window method, we measured irradiation-induced changes in the vascular permeability and cell interactions in microcirculation networks of the rat pia mater; the same effects were monitored in the cremaster muscle as a control. The closed cranial window has many advantages, including long-term direct visualization of microcirculation. The method allows for repeated testing of the same vessel or network, thereby reducing variability. The method also allows for measurement of permeability changes and the accompanying leukocyte–endothelial cell interactions in the same network or vessel, which permits correlative studies of these phenomena. However, this method is not without challenges. The optical conditions are difficult, because the brain is three-dimensional and its parenchyma is more complex than the thinner, flatter peripheral tissues. To overcome this limitation, we performed a dynamic background subtraction. The background is dynamically related to vessel intensity, and changes in intensity were determined by eliminating the effects of neighboring and underlying vessels. We applied this method to studying the effects of ionizing radiation on the blood–brain barrier (BBB) permeability and cell interactions and the modulation of these effects by anti-ICAM-1 antibodies. Our results demonstrate that this method is sensitive to changes in these properties of the BBB.

Static Magnetic Field and Verapamil Effect on Baroreflex Stimulus-Induced Microcirculatory Responses

Arterial baroreceptors importantly evolved in blood pressure regulation with significant clinical consequences. We studied the less explored direct effect of the arterial baroreflex on regional microcirculation. Fifty-one experiments were performed in conscious rabbits to investigate the relationship between microcirculation and arterial baroreflex subjected to stimulation with either 0.35 T static magnetic field (SMF) and/or the calcium channel blocker, verapamil. Mean femoral artery blood pressure (MAP), heart rate (HR), and a microphotoelectric plethysmogram (MPPG) of the ear lobe skin microcirculatory network were simultaneously recorded during 120 and 140 min experiments. Baroreflex sensitivity (BRS) was assessed on the basis of the HR/MAP relationship during vasodilator (sodium nitroprusside) or vasoconstrictor (phenylephrine) drug i.v. bolus injections and by power spectral analysis estimating the transfer function from MAP to HR before and after 40 min of 0.35 T SMF (Nd2-Fe14-B magnets) local exposure to sinocarotid baroreceptors and/or verapamil infusion (20 µg/kg/min). We found significant positive correlation between MPPG and BRS (R = 0.44, p = 0.02, n = 28) indicating participation of the baroreflex regulatory mechanism in microcirculation. Both SMF and verapamil increased baroreflex stimulus-induced microcirculatory responses (p < 0.01) indicating augmentation of baroreceptor capacity to regulate microcirculation. The simultaneous application of SMF and verapamil did not affect microcirculatory response suggesting Ca2+ channels as a possible site of SMF impact. Pharmacological and nonpharmacological modulation of the baroreflex stimulus-induced microcirculatory responses implies new possibilities to improve microcirculation in target organs with potential clinical implementation.

Impact of aging on the body’s vascular system

In this review, the effect of aging on the body’s vascular system is considered in terms of potential mechanisms involved in target organ damage. First, the effects of aging on body fluid compartments, including changes that occur in subdivisions of the interstitial space (quite heterogeneous among organs), are described, with particular reference to the macromolecular composition of the fluid compartments. Second, the structure and function of different segments of the vascular system during aging are examined, with emphasis on: (1) large arterial conduits responsible for isolated systolic hypertension; (2) arteries most responsible for peripheral resistance (the “resistance arteries”); (3) microcirculation networks, including the vasa vasorum; and (4) large collecting veins that can have such an important effect on the cardiac output. Third, a detailed discussion is provided of the heterogeneous macromolecular composition of interstitial fluid compartments that are involved in the critical traffic of vital substrates, including pharmacologic agents, in transit from the systemic circulation to the various organs. The strategic position of interstitial fluid compartments, situated as they are between microcirculation networks and vital organs, is considered to be critically involved in the morbidity and mortality caused by the vascular diseases afflicting elderly persons. Finally, with respect to “physiological” and/or “morbid” aging, a re-examination is undertaken of the target organ damage observed in elderly individuals who suffer from isolated systolic hypertension, type II diabetes mellitus, peripheral vascular disease, chronic heart failure, and renal failure. Potentially new and noninvasive approaches available to clinicians for early detection of large artery rigidity are considered, along with the possible benefits of nonpharmacologic and/or pharmacologic interventions.

Impact of aging on the body’s vascular system

In this review, the effect of aging on the body’s vascular system is considered in terms of potential mechanisms involved in target organ damage. First, the effects of aging on body fluid compartments, including changes that occur in subdivisions of the interstitial space (quite heterogeneous among organs), are described, with particular reference to the macromolecular composition of the fluid compartments. Second, the structure and function of different segments of the vascular system during aging are examined, with emphasis on: (1) large arterial conduits responsible for isolated systolic hypertension; (2) arteries most responsible for peripheral resistance (the “resistance arteries”); (3) microcirculation networks, including the vasa vasorum; and (4) large collecting veins that can have such an important effect on the cardiac output. Third, a detailed discussion is provided of the heterogeneous macromolecular composition of interstitial fluid compartments that are involved in the critical traffic of vital substrates, including pharmacologic agents, in transit from the systemic circulation to the various organs. The strategic position of interstitial fluid compartments, situated as they are between microcirculation networks and vital organs, is considered to be critically involved in the morbidity and mortality caused by the vascular diseases afflicting elderly persons. Finally, with respect to “physiological” and/or “morbid” aging, a re-examination is undertaken of the target organ damage observed in elderly individuals who suffer from isolated systolic hypertension, type II diabetes mellitus, peripheral vascular disease, chronic heart failure, and renal failure. Potentially new and noninvasive approaches available to clinicians for early detection of large artery rigidity are considered, along with the possible benefits of nonpharmacologic and/or pharmacologic interventions.

Interaction of leptin with gastric myofibroblast transdifferentiation in Helicobacter pylori-infected Mongolian gerbils: the effect of rebamipide.

Our recent histochemical studies have revealed the marked increase of myofibroblasts in the Helicobacter pylori-infected Mongolian gerbil fundic mucosa, while the mediators, which facilitate the conversion of fibroblasts to the myofibroblasts have remained unknown. The present study was undertaken to clarify the alteration of leptin in the control and H. pylori-infected Mongolian gerbil stomach. The effector sites of rebamipide were also investigated in relation to leptin. The localization of leptin was investigated by the indirect immunofluorescence. Plasma leptin levels were determined by ELISA method. The localization of 3H-rebamipide binding sites was investigated by autoradiography. Serum leptin content in H. pylori-infected Mongolian gerbils was significantly increased. The presence of leptin immunoreactivity was recognized in the endothelial cells of the microcirculatory network and very weakly in the glandular cells in the control group, while in the H. pylori-infected group leptin was markedly recognized in the mesenchymal cells. Rebamipide bound to the fibroblasts and surface mucous cells and decreased the leptin immunoreactivity in the gastric mucosa. Leptin was mostly found in the mesenchymal cells. Rebamipide administration brought about the decrease of leptin in the gastric mucosaof the H. pylori-infected gerbils.

Assessment of efficacy of bothropic antivenom therapy on microcirculatory effects induced by Bothrops jararaca snake venom

Intravenous administration of antibothropic antivenom (BAv) neutralises the systemic effects, but does not efficiently reverse the local symptoms elicited by the Bothrops jararaca venom (BjV). The mechanisms involved in this poor protection have not been clarified. In this work, intravital microscopy studies were carried out to determine the efficacy of different schedules of BAv treatment on local effects evoked by topical application of BjV in the microcirculatory network of the internal spermatic fascia of Wistar rats. Results demonstrated that BAv administration 15 min before, simultaneously with, or 15 min after BjV application did not totally reverse the local symptoms, represented by disturbances of coagulation, development of haemorrhage lesions, vascular permeability increase and increment on leukocyte–endothelium interactions. This lack of effectiveness neither reflects an inadequate amount of specific antibodies in the antivenom against toxins responsible for local effects nor an insufficient dose of circulating BAv during the assays. Administration of fluorescein isothiocyanate (FITC) labelled-BAv showed the dynamics of distribution of the antivenom in the microcirculatory network. Images obtained from prior and simultaneously treated animals showed that the antivenom remains at luminal side of vessels before venom application, and the latency time to antivenom leakage is coincidental to that for local effects evoked by the venom. In addition, images from posterior treatment demonstrated that the intense alterations in the microcirculatory network impair antivenom distribution at the site of injection. Together, our data show that the lack of effectiveness of antivenom therapy is due to impaired and delayed venom and antivenom interaction at the site of injury.

Mechanisms and consequences of large artery rigidity.

In this review paper, the classical and more recently described mechanisms responsible for the structural and functional characteristics of large artery rigidity are described. Mostly important, these characteristics appear to be non-specific to the primary disease process involved in arterial hypertension, diabetes mellitus, dyslipidemia, congestive heart failure, chronic uremia, and perhaps senescence, including vascular dementia. Nonspecific in terms of aetiology, the vasculopathy encountered in these diseases exhibits common structural and functional abnormalities. The identification of such abnormalities could well become the target of potent nonpharmacological and (or) pharmacological interventions capable of preventing or retarding morbidity and mortality. The structural characteristics responsible for large artery rigidity include smooth muscle cell hypertrophy, matrix collagen deposition, and recently described, dysfunction in proteoglycan metabolism. Functional abnormalities, such as bradykinin-dependent hyper-reactivity of smooth muscle cells and vasa vasorum microcirculation network disturbances, also appear to alter aortic wall rigidity. The physiopathology of target organ damage is then revisited, based on endothelial dysfunction, documented in large and resistance arteries, as well as in microcirculation networks, where altered permeability to macromolecules leads to interstitial matrix disorganization and cell damage. The clinical evaluation of large artery rigidity is described, and one of the noninvasive methods, evaluation of pulse-wave velocity, is validated in normal conditions and in disease processes. Finally, non-pharmacological and pharmacological therapeutic measures are presented, and includes physical exercise to reduce insulin resistance, and renin-angiotensin-II-aldosterone modulators.

Determination of size distribution of elliptical microvessels from size distribution measurement of their section profiles.

In transmission electron microscopy, microvessels (MVs) are studied as profiles on ultrathin sections. To determine MV sizes from measurements made on MV profiles, an assumption must be made about MV shape, a circular cylinder being used to approximate the latter on limited lengths. However, this model is irrelevant in case MVs have some flatness. The elliptical cylinder model is preferable, although relationships between the cylinder profile (two-dimensional; 2D) and its true (three-dimensional; 3D) sizes are not yet known. We have obtained the 2D/3D functions that express the relationships between such profile sizes as the minor radius (Y), major radius (X), axial ratio (X/Y), area (S), and perimeter (P) on the one hand, and the corresponding MV sizes (Y(0), X(0), X(0)/Y(0), S(0), and P(0)) on the other. The 2D/3D functions make it possible to derive elliptical MV sizes from section profile size distributions, probability density functions (PDFs) for the latter being determined. We have applied the 2D/3D functions in studying axial ratios of thyroid hemocapillaries. A factual X/Y frequency histogram has been constructed and fitted by theoretical X/Y PDFs plotted for different sets of capillary sizes. The thyroid capillaries have been revealed to be clustered, 72.7% of them having X(0)/Y(0) approximately 1.6, 17.6%, X(0)/Y(0) approximately 1.0, and 9.7%, X(0)/Y(0) approximately 3.2. The proposed technique is instrumental in precise modeling of microcirculatory network geometry.

EDHF, but not NO or prostaglandins, is critical to evoke a conducted dilation upon ACh in hamster arterioles

Vasomotor reactions upon focal stimulation of arterioles have been shown to be conducted along the vascular wall. Such a conduction, which is assumed to reflect the spread of electrical signals, may contribute to coordination of responses within a vascular segment. We aimed to identify which endothelial autacoid(s) act as mediators of the local and conducted dilator responses, respectively. To this end, arterioles in the hamster cremaster microcirculation were locally stimulated with endothelium-dependent [acetylcholine (ACh)] or endothelium-independent dilators [sodium nitroprusside (SNP)], and the resulting changes in diameter were measured using a videomicroscopy technique at the site of application and up to 1.4 mm upstream at distant sites. Experiments were also performed after blockade of nitric oxide (NO) synthase, cyclooxygenase, P-450 monooxygenase, or K(+) channels. Dilations upon ACh (71 +/- 3%) were conducted rapidly (<1 s) to upstream sites (at 1.4 mm: 37 +/- 5%). Although the NO donor SNP induced a similar local dilation (71 +/- 7%), this response was not conducted. Maximal amplitudes of ACh-induced dilations were not attenuated after inhibition of NO synthase and cyclooxygenase at the local and remote sites. However, additional treatment with a P-450 monooxygenase blocker (sulfaphenazole) strongly attenuated the local response (from 62 +/- 9 to 17 +/- 5%) and abrogated dilations at distant sites (at 0.67 mm: from 23 +/- 4% to 4 +/- 3%). Likewise, 17-octadecynoic acid strongly attenuated local and remote responses. Blockers of Ca(2+)-dependent K(+) channels (charybdotoxin or iberiotoxin) attenuated dilations at the local and remote sites after focal application at the ACh stimulation site. In marked contrast, treatment of the upstream site with these blockers was without any effect. We conclude that upon local stimulation with ACh, a cytochrome P-450 monooxygenase product is generated that induces local dilation via the activation of Ca(2+)-dependent K(+) channels and initiates conduction of the dilation. In contrast to the local site, neither activation of these K(+) channels nor the synthesis of NO or prostaglandins is necessary to dilate the arterioles at remote, distant sites. This suggests that endothelium-derived hyperpolarizing factor serves as an important mediator to initiate conducted dilations and, by doing so, may act as a key player in the coordination of arteriolar behavior in the microcirculatory network.

Dopexamine attenuates microvascular perfusion injury of the small bowel in pigs induced by extracorporeal circulation

Cardio-thoracic surgery with the use of extracorporeal circulation may lead to an impairment of splanchnic perfusion. The aim of this study was to investigate the effect of dopexamine on gastrointestinal microvascular perfusion failure due to extracorporeal circulation. Twenty landrace pigs served as laboratory animals. A loop of the terminal ileum was exteriorized for microscopic observation. In 13 animals a partial left-heart bypass (pLHB), with a non-pulsatile pump flow of approximately 50% of the cardiac output, was established for 2 h. Seven animals received a continuous i.v. infusion of 3 micrograms kg-1 min-1 dopexamine from the beginning of pLHB to the end of the experiment. Seven sham-operated animals served as controls. The microcirculatory network was analysed by means of intra-vital microscopy prior to, during pLHB, and 2 h after bypass. Despite normal haemodynamics measured by arterial pressure and cardiac output, pLHB led to significant impairment of microvascular perfusion characterized by arteriolar vasoconstriction, reduction of functional capillary density (FCD) to 30% 2 h after weaning off bypass and diminished blood-cell velocities in submucous venules. Dopexamine attenuated this perfusion impairment, preventing arteriolar vasoconstriction. FCD remained normal. Our data demonstrate that treatment with the vasoactive drug dopexamine leads to a significant reduction of the perfusion injury of the small bowel.

Influence of steroids on microvascular perfusion injury of the bowel induced by extracorporeal circulation

Background. Extracorporeal circulation is associated with gastrointestinal complications. By means of intravital microscopic methods, we investigated whether preoperative treatment with steroids can attenuate the impairment of the bowel microcirculation. Methods. In 20 pigs, a partial left heart bypass (pLHB) was established. A loop of the terminal ileum was exteriorized for intravital-microscopic observation. Seven sham-operated animals served as controls. In 13 animals, pLHB was established for 2 hours with a flow rate of 2,000 mL per minute; 7 of the animals received 20 mg/kg body weight prednisolone preoperatively. The microcirculatory network was analyzed before, during pLHB, and 2 hours after bypass. Results. Despite unchanged macro-hemodynamics, pLHB resulted in a significant microvascular perfusion injury of the small bowel. Arteriolar vasoconstriction and a reduction of perfused capillaries per unit area (functional capillary density) to 30% of prebypass values could be found. Blood cell velocities were reduced in submucuous collecting venules. In the steroid-treated animals, the functional capillary density remained normal. In addition, arteriolar vasoconstriction could be prevented. Conclusions. Treatment with prednisolone largely prevents the microcirculatory alterations in the small bowel induced by extracorporeal circulation.

Alterations of the Microcirculatory Network during the Clearance of Epimastigote Forms of Trypanosoma cruzi: An Intravital Microscopic Study

Alterations of the Microcirculatory Network during the Clearance of Epimastigote Forms of Trypanosoma cruzi: An Intravital Microscopic Study

Alterations of the microcirculatory network during the clearance of epimastigote forms of Trypanosoma cruzi: an intravital microscopic study.

The distribution of epimastigote forms of Trypanosoma cruzi in the microcirculatory network and the vessel alterations were observed using an intravital microscopy technique. Immediately after intravenous inoculation of 2 x 10(6) epimastigote suspension into normal mice, parasites were seen as circulating clumps, and their retention at some sites of the endothelium of venules and capillaries was observed. Injection of 2 x 10(7) and 2 x 10(8) parasite suspensions induced, respectively, intermittent or total stasis of venules and capillaries, probably via obstruction by clumping. The mobility of epimastigotes in the clumps indicates that parasites were alive in the lumen of vessels. The retention of clumps in the capillaries, although intense, could only be observed when labeled parasites were inoculated. These results suggest that the rapid clearance of epimastigote forms of T. cruzi from the blood circulation of mice may be due to the retention of parasites to the endothelium of venules and capillaries that, in turn, may facilitate phagocytosis. This may be a mechanism by which mice are able to eliminate epimastigote forms from the circulation. These findings are consistent with our previous observations showing that epimastigotes are not lysed by complement activation but are phagocytosed and destroyed by a distinct population of blood cells.

Pressure and Microcirculatory Effects of Treatment with Lercanidipine in Hypertensive Patients and in Vascular Patients with Hypertension

The aim of this study was to evaluate the macrocirculatory and microcirculatory effects of treatment with lercanidipine, a new antihypertensive agent acting both on blood pressure and microcirculation in patients with moderate essential hypertension and without vascular disease and in patient with hypertension and vascular disease. In hypertensive subjects target-organ damage associated with high blood pressure may now be objectively documented by noninvasive tests. These alterations constitute a model to evaluate not only the pressure effects of antihypertensive treatment but also the normalization of the peripheral microcirculatory network. With color duplex scanning, flow velocity in the central retinal artery and retinal flow velocity can be measured and with use of laser-Doppler-flowmetry, it is also possible to evaluate microcirculation alterations in hypertensive subjects. These evaluation methods are completely noninvasive and may be used to assess the microcirculatory effects of antihypertensive drugs.

Microcirculatory network structures and models.

Terminal vascular beds exhibit a high degree of heterogeneity. Pertinent parameters are nonlinearly related, and their distributions are not independent. The classical "typical vessel" approach using averaged values for different vessel classes may not lead to a correct understanding of physiology and pathophysiology of terminal vascular beds. Such problems can be avoided by studying microcirculatory functions at the network level using a combination of experiments and theoretical models. In this approach, distributions and relationships of pertinent parameters are measured in vivo, leading to the development of comprehensive databases. Such databases can be analyzed and complemented by suitable mathematical models, permitting estimation of parameters that are difficult to measure, and critical assessment of quantitative theories and hypotheses for microvascular function. This collaborative process between experimentally and theoretically oriented investigators may be facilitated in the future by the development of web-based repositories of experimental data and theoretical models.

Microvasculature, blood flow, and vasoreactivity in rabbit sinus mucosa after surgery.

To study the circulatory integrity of the sinus mucosa following surgery, the vascular anatomy, blood flow, and vasoconstrictor response of the regenerated microcirculatory network were analyzed. Forty-six New Zealand White rabbits were operated on unilaterally with either a modified radical operation (MRO) or middle meatal antrostomy (MMA), using the nonoperated sinus for control purposes. After surgery, the animals were left to heal for 1 month. Vascular casts were prepared with a low-viscosity methyl methacrylate resin and studied by scanning electron microscopy. Blood flow was measured by means of radiolabeled microspheres (tin 113 [113Sn]). The vasoconstrictor response to oxymetazoline at increasing concentrations was measured with laser Doppler flowmetry. The number of vessels increased significantly in the regenerated mucosa. The vascular casts displayed a rich microcirculation with local signs of angiogenesis. However, there was no difference in blood flow between the operated cavities and their control sides. Following MRO the regenerated mucosa was more sensitive to the vasoconstrictor effect of oxymetazoline, compared with the control side. This difference was not evident in the MMA-operated sinuses. In this model, surgery does not seriously interfere with the sinus blood flow, although the regenerated mucosa did display an altered vasoreactivity. These findings should be considered in relation to the effects of surgery intended to limit local inflammation and to ensure the ventilation of the sinuses.

The blood vessel, linchpin of diabetic lesions

The morbidity and mortality associated with diabetes mellitus are essentially related to the vascular lesions that develop over time in this condition. Both the macrocirculation and microcirculation are involved, and as a consequence, vital organs such as the brain, retina, heart, and kidney and the limbs become damaged. Because microalbuminuria represents the earliest and probably most sensitive indication of endothelial dysfunction in diabetes mellitus, the results of pharmacologic intervention with angiotensin-converting enzyme inhibitors, which treat glomerular hypertension were the first indication of potential beneficial effects in reducing diabetic nephroplasty. The nature of endothelial dysfunction related to diabetes is probably not homogeneous, since microcirculation networks are affected at different periods and with variable intensity. This appears to be the case for the aorta, the heart, segments of the digestive tract, the skin, and the skeletal muscle, the largest consumer of insulin. Although the aorta and large arteries contain a small portion of the total blood volume, their distribution of blood flow (pulse pressure) to peripheral organs may affect endothelial function in the microcirculation. Changes in the structure of conduit arteries, partly responsible for the alteration in compliance characteristics, could well be related to the way these arteries are fed by the vasa vasorum system. This report describes a new in vitro approach to examine capillary permeability in normal and alloxan-induced diabetic rabbits. Preliminary results indicate that the size of terminal arterioles of the vasa vasorum (increased diameter) and the capillary permeability to albumin (markedly enhanced) in this specialized network are profoundly affected in the thoracic aorta obtained from diabetic animals. Albumin extravasation into the interstitial fluid compartment of the aorta is likely to lead to structural and physicochemical changes: in fact, removal of interstitial macromolecules via lymphatic drainage is poor in the blood vessel wall of large arteries. This experimental approach is likely to be useful in the exploration of medications affecting the structure and function of conduit vessels.