A multiscale framework for defining homeostasis in distal vascular trees: applications to the pulmonary circulation

Biomechanics and Modeling in Mechanobiology - Pulmonary arteries constitute a low-pressure network of vessels, often characterized as a bifurcating tree with heterogeneous vessel mechanics....     

Divergent contractile and structural responses of the murine PKC-epsilon null pulmonary circulation to chronic hypoxia

Loss of PKC-epsilon limits the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) in the mouse. Therefore, we hypothesized that loss of PKC-epsilon would decrease the contractile and/or structural response of the murine pulmonary circulation to chronic hypoxia (Hx). However, the pattern of lung vascular responses to chronic Hx may or may not be predicted by the acute HPV response. Adult PKC-epsilon wild-type (PKC-epsilon(+/+)), heterozygous null, and homozygous null (PKC-epsilon(-/-)) mice were exposed to normoxia or Hx for 5 wk. PKC-epsilon(-/-) mice actually had a greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to chronic Hx than PKC-epsilon(+/+) mice. In contrast to the augmented PA pressure and RV hypertrophy, pulmonary vascular remodeling was increased less than expected (i.e., equal to PKC-epsilon(+/+) mice) in both the proximal and distal PKC-epsilon(-/-) pulmonary vasculature. The contribution of increased vascular tone to this pulmonary hypertension (PHTN) was assessed by measuring the acute vasodilator response to nitric oxide (NO). Acute inhalation of NO reversed the increased PA pressure in hypoxic PKC-epsilon(-/-) mice, implying that the exaggerated PHTN may be due to a relative deficiency in nitric oxide synthase (NOS). Despite the higher PA pressure, chronic Hx stimulated less of an increase in lung endothelial (e) and inducible (i) NOS expression in PKC-epsilon(-/-) than PKC-epsilon(+/+) mice. In contrast, expression of nNOS in PKC-epsilon(+/+) mice decreased in response to chronic Hx, while lung levels in PKC-epsilon(-/-) mice remained unchanged. In summary, loss of PKC-epsilon results in increased vascular tone, but not pulmonary vascular remodeling in response to chronic Hx. Blunting of Hx-induced eNOS and iNOS expression may contribute to the increased vascular tone. PKC-epsilon appears to be an important signaling intermediate in the hypoxic regulation of each NOS isoform.     

Prone position reverses gravitational distribution of perfusion in dog lungs with oleic acid-induced injury

Although oxygenation improves in patients with the adult respiratory distress syndrome and in animals with oleic acid- (OA) induced acute lung injury when they are turned from the supine to the prone position, the mechanism(s) by which this improvement occurs is not known. Several groups have speculated that this improvement results from preferential edema accumulation in the dorsal lung regions and redistribution of perfusion away from these regions when the patients are turned to the prone position. We used radiolabeled microspheres to measure the regional distribution of perfusion (Qr) to the dorsal, mid, and ventral lungs of eight dogs in vivo in the supine and prone positions, before and after inducing acute lung injury with OA, and correlated the Qr observed after injury with the degree of regional extravascular lung water (EVLWr). Before OA, Qr increased along the gravitational gradient when the animals were supine but was more uniformly distributed when they were prone. After OA, Qr again followed a gravitational gradient when the animals were supine but was preferentially distributed to the nondependent regions when they were prone. EVLWr was similar in all regions, regardless of whether OA was injected when the animals were supine or prone. The gravitational Qr gradient is markedly reduced in the prone position, both before and after lung injury. The prone position-induced improvement in oxygenation is not the result of redistribution of Qr away from areas in which edema preferentially develops.     

Gill circulation: regulation of perfusion distribution and metabolism of regulatory molecules

The fish gill is the primary regulatory interface between internal and external milieu and a variety of neurocrine, endocrine, paracrine, and autocrine signals coordinate and control gill functions. Many of these messengers also affect gill vascular resistance, and they, in turn, may be inactivated (or activated) by branchial vessels. Few studies have critically addressed how flow is distributed within the gill filament, the physiological consequences thereof, or the impact of gill hormone metabolism on gill and systemic homeostasis. In most fish, the entire cardiac output perfuses the arterioarterial pathway, and this network probably accounts for the majority of passive- and stimulus-induced changes in vascular resistance. The in-series arrangement of the extensive gill microcirculation with systemic vessels is also indicative of a high capacity for metabolism of plasma-borne messengers as well as xenobiotics. Adenosine, arginine vasotocin (AVT), and endothelin (ET) are the most potent gill constrictors identified to date, and all decrease lamellar perfusion. Perhaps not surprising, they are also inactivated by gill vessels. Acetylcholine favors perfusion of the alamellar filamental vasculature, although the physiological relevance of acetylcholine-mediated responses remains unclear. Angiotensin, bradykinin, urotensin, natriuretic peptides, prostaglandins, and nitric oxide are vasoactive to varying degrees, but their effects on intrafilamental blood flow are unknown. If form befits function, then the complex vascular anatomy of the gill suggests a level of regulatory sophistication unparalleled in other vertebrate organs. Resolution of these issues will be technically challenging but unquestionably rewarding.     

A model for hypoxic constriction of the pulmonary circulation

The detailed anatomic and biodynamic data provided for the cat lung by Zhuang et al. (J. Appl. Physiol. 55: 1341-1348, 1983) allowed pressure-flow curves for the normal lung to be generated. This model has been modified to permit the stimulation of the pressure and flow distribution effects of hypoxic pulmonary vasoconstriction for a two-compartment lung and generalized to allow comparison with the experimental results from dogs (and probably other species). Hypoxic pulmonary vasoconstriction is simulated by reduction of the initial diameter of the smallest six orders of pulmonary arteries. Expressions are presented that relate the alveolar and mixed-venous O2 tensions to a graded constriction of these vessels. In addition, the diameter of the capillary sheet and the six small arteries is defined with a maximum diameter at a transmural pressure of 20 cmH2O. Pressure-flow curves are derived for any combination of alveolar and mixed-venous O2 tension, alveolar and pleural pressure, left atrial pressure, and hematocrit. The two-compartment model is solved by an iterative procedure to identify the distribution of the flow and the resulting pulmonary arterial pressure when the compartments differ by size, hypoxic constriction, or other imposed conditions. The results of the model are compared with those from a variety of experimental preparations. It is concluded that the model is useful for identifying the quantitative causes of changes in the response to hypoxic pulmonary vasoconstriction and for the exploration of the functional influence of mechanical properties of the vasculature.     

Evaluation of structural and evolutionary contributions to deleterious mutation prediction

Methods for automated prediction of deleterious protein mutations have utilized both structural and evolutionary information but the relative contribution of these two factors remains unclear. To address this, we have used a variety of structural and evolutionary features to create simple deleterious mutation models that have been tested on both experimental mutagenesis and human allele data. We find that the most accurate predictions are obtained using a solvent-accessibility term, the C(beta) density, and a score derived from homologous sequences, SIFT. A classification tree using these two features has a cross-validated prediction error of 20.5% on an experimental mutagenesis test set when the prior probability for deleterious and neutral cases is equal, whereas this prediction error is 28.8% and 22.2% using either the C(beta) density or SIFT alone. The improvement imparted by structure increases when fewer homologs are available: when restricted to three homologs the prediction error improves from 26.9% using SIFT alone to 22.4% using SIFT and the C(beta) density, or 24.8% using SIFT and a noisy C(beta) density term approximating the inaccuracy of ab initio structures modeled by the Rosetta method. We conclude that methods for deleterious mutation prediction should include structural information when fewer than five to ten homologs are available, and that ab initio predicted structures may soon be useful in such cases when high-resolution structures are unavailable.     

Distensibility and pressure-flow relationship of the pulmonary circulation. I. Single-vessel model

To ascertain the relative contributions of vascular distensibility and nonhomogeneous behavior within the pulmonary circulation to the distinctive nonlinear relationship between inflow pressure (Pin) and flow [pressure-flow (P-F) relationship] and between Pin and outflow pressure (Pout) at constant flow (Pin-Pout relationship), we developed a multibranched model in which the elastic behavior of, and forces acting on, individual branches can be varied independently. The response of the multibranched model is described in the companion article (J. Appl. Physiol. 68: 1514-1527, 1990). Here we describe the methods used and the responses of single components of the larger model. Perivascular pressure is modeled as a function of intravascular and transpulmonary pressures (Pv and Ptp, respectively) and vessel length as a function of lung volume. These and the relationship between vascular area (A) and transmural pressure (Ptm) were modeled primarily from the dog data of Smith and Mitzner (J. Appl. Physiol. 48: 450-467, 1980). Vasomotor tone is modeled as a radial collapsing pressure (Pt) in the same plane as Ptm. In view of lack of information about the relationship between Pt and A for a given active state, different patterns were assumed that span a wide range of possible relationships. The P-F and Pin-Pout relationships of single vessels were very similar to those reported for the entire intact circulation. Of note, the slope of the Pin-Pout relationship in the low Pout range (0-5 Torr) was very low (less than 0.25) and increased gradually with Pout toward unity. Vasomotor tone caused an apparent parallel shift in the P-F relationship in the physiological flow range of the dog (2-8 l/min) regardless of the pattern used to model the Pt vs. A relationship; different patterns affected the P-F relationship only over the low flow range before the parallel shift was established.     

Distensibility and pressure-flow relationship of the pulmonary circulation. II. Multibranched model

The contribution of distensibility and recruitment to the distinctive behavior of the pulmonary circulation is not known. To examine this question we developed a multibranched model in which an arterial vascular bed bifurcates sequentially up to 8 parallel channels that converge and reunite at the venous side to end in the left atrium. Eight resistors representing the capillary bed separate the arterial and venous beds. The elastic behavior of capillaries and extra-alveolar vessels was modeled after Fung and Sobin (Circ. Res. 30: 451-490, 1972) and Smith and Mitzner (J. Appl. Physiol. 48: 450-467, 1980), respectively. Forces acting on each component are modified and calculated individually, thus enabling the user to explore the effects of parallel and longitudinal heterogeneities in applied forces (e.g., gravity, vasomotor tone). Model predictions indicate that the contribution of distensibility to nonlinearities in the pressure-flow (P-F) and atrial-pulmonary arterial pressure (Pla-Ppa) relationships is substantial, whereas gravity-related recruitment contributes very little to these relationships. In addition, Pla-Ppa relationships, obtained at a constant flow, have no discriminating ability in identifying the presence or absence of a waterfall along the circulation. The P-F relationship is routinely shifted in a parallel fashion, within the physiological flow range, whenever extra forces (e.g., lung volume, tone) are applied uniformly at one or more branching levels, regardless of whether a waterfall is created. For a given applied force, the magnitude of parallel shift varies with proportion of the circulation subjected to the added force and with Pla.     

Measurement of pulsatile flows and variable volumes by bolus injection of indicator in a model of the pulmonary circulation

The reliability and accuracy of the bolus injection-dye dilution technique were assessed for a physiological range of frequencies (13-49 min-1) and stroke volumes (60-160 ml) on a glass model where flows and volumes varied as a preset function of time (n = 320). We found that the technique overestimates flow by about 8% with a 95% confidence interval of +/- 10% for one measurement. Mean transit times are accurate within a +/- 7% confidence interval for one measurement. In a time-dependent flow and volume system this technique measures the mean volume as related to time with fluctuations up to +/- 30% around the mean. Results are independent of time and site of injection. The double injection-single sampling technique gives results that are equivalent to those obtained by single injection and sampling of dye.     

The Catch model: a solution to the problem of saliency in facial features

The goal of the present paper is to propose a solution to the 'saliency problem' which has been raised in regard to Rakover and Cahlon's (1989) Catch model for identifying a previously seen target face (Ft). In contrast to real life situations, the Catch model assigned the same weight to different facial dimensions and values. Mathematical proofs, reanalyses of the results of three experiments reported in Rakover and Cahlon, and the analysis of the results of a new experiment show that this proposal expands and improves the Catch model.