Christopher M. Quick

Abnormal pattern of Tie-2 and vascular endothelial growth factor receptor expression in human cerebral arteriovenous malformations

OBJECTIVEHuman cerebral arteriovenous malformations (AVMs) are speculated to result from abnormal angiogenesis. Vascular endothelial growth factor receptors (VEGF-Rs) and Tie-2 play critical roles in vasculogenesis and angiogenesis. We hypothesized that the abnormal vascular phenotype of AVMs may be associated with abnormal expression of VEGF-Rs and Tie-2. METHODSWe measured the expression of Tie-2, VEGF-R1, and VEGF-R2 in AVMs and normal brain tissue, using immunoblotting. To assess active vascular remodeling, we also measured endothelial nitric oxide synthase expression. CD31 expression was used to control for endothelial cell mass for Tie-2, VEGF-Rs, and endothelial nitric oxide synthase. Immunoblotting data were presented as relative expression, using normal brain tissue values as 100%. RESULTSCD31 was expressed to similar degrees in AVMs and normal brain tissue (99 ± 29% versus 100 ± 20%, mean ± standard error, P = 0.98). Tie-2 expression was markedly decreased in all AVMs, compared with normal brain tissue (16 ± 9% versus 100 ± 37%, P = 0.04). VEGF-R1 expression was decreased in four of five AVMs, but the difference between the mean values was not significant (35 ± 8% versus 100 ± 42%, P = 0.14). VEGF-R2 expression was decreased in all AVMs, compared with normal brain tissue (28 ± 6% versus 100 ± 29%, P = 0.03). There was no difference in endothelial nitric oxide synthase expression between AVMs and normal brain tissue (106 ± 42% versus 100 ± 25%, P = 0.91). CONCLUSIONAVM vessels exhibited abnormal expression of Tie-2 and VEGF-Rs, both of which may contribute to the pathogenesis of AVMs.

Evidence of increased endothelial cell turnover in brain arteriovenous malformations.

OBJECTIVEWe hypothesized that human brain arteriovenous malformations (BAVMs) are nonstatic vascular lesions with active angiogenesis or vascular remodeling. To test this hypothesis, we assessed endothelial cell turnover in BAVMs. METHODSWe identified nonresting endothelial cells by use of immunohistochemistry for the Ki-67 antigen. From archived paraffin blocks, we selected BAVM vessels without intravascular thrombosis or embolic material in areas nonadjacent to the nidus edge. For controls, we used 50- to 100-&mgr;m diameter cortical vessels from temporal lobe cortex removed for epilepsy treatment. The Ki-67 index was calculated as a percentage of Ki-67-positive endothelial cells. The data were analyzed by the nonparametric Mann-Whitney test and reported as mean ± standard deviation. RESULTSThirty-seven specimens that met the above criteria were selected. There were 26 ± 15 vessels counted in each BAVM specimen versus 18 ± 5 in each control cortex (n = 5). The mean Ki-67 index was higher for BAVM vessels than control cortical vessels (0.7 ± 0.6 versus 0.1 ± 0.2%;P = 0.005), which represented an approximately seven-fold increase in the number of nonresting endothelial cells. In the BAVM group, there was a trend for younger patients to have a wider variation and higher Ki-67 index than older patients; no trend was evident in the control group. CONCLUSIONCompared with control vessels, BAVM vessels have higher endothelial cell turnover, which suggests the presence of active angiogenesis or vascular remodeling in BAVMs.

Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema

Myocardial interstitial edema forms as a result of several disease states and clinical interventions. Acute myocardial interstitial edema is associated with compromised systolic and diastolic cardiac function and increased stiffness of the left ventricular chamber. Formation of chronic myocardial interstitial edema results in deposition of interstitial collagen, which causes interstitial fibrosis. To assess the effect of myocardial interstitial edema on the mechanical properties of the left ventricle and the myocardial interstitium, we induced acute and chronic interstitial edema in dogs. Acute myocardial edema was generated by coronary sinus pressure elevation, while chronic myocardial edema was generated by chronic pulmonary artery banding. The pressure-volume relationships of the left ventricular myocardial interstitium and left ventricular chamber for control animals were compared with acutely and chronically edematous animals. Collagen content of nonedematous and chronically edematous animals was also compared. Generating acute myocardial interstitial edema resulted in decreased left ventricular chamber compliance compared with nonedematous animals. With chronic edema, the primary form of collagen changed from type I to III. Left ventricular chamber compliance in animals made chronically edematous was significantly higher than nonedematous animals. The change in primary collagen type secondary to chronic left ventricular myocardial interstitial edema provides direct evidence for structural remodeling. The resulting functional adaptation allows the chronically edematous heart to maintain left ventricular chamber compliance when challenged with acute edema, thus preserving cardiac function over a wide range of interstitial fluid pressures.

True Arterial System Compliance Estimated From Apparent Arterial Compliance

AbstractA new method has been developed to estimate total arterial compliance from measured input pressure and flow. In contrast to other methods, this method does not rely on fitting the elements of a lumped model to measured data. Instead, it relies on measured input impedance and peripheral resistance to calculate the relationship of arterial blood volume to input pressure. Generally, this transfer function is a complex function of frequency and is called the apparent arterial compliance. At very low frequencies, the confounding effect of pulse wave reflection disappears, and apparent compliance becomes total arterial compliance. This study reveals that frequency components of pressure and flow below heart rate are generally necessary to obtain a valid estimate of compliance. Thus, the ubiquitous practice of estimating total arterial compliance from a single cardiac cycle is suspect under most circumstances, since a single cardiac cycle does not contain these frequencies.

Lack of flow regulation may explain the development of arteriovenous malformations

Abstract In the normal vasculature, vessels of widely different sizes maintain shear stress within a narrow range. Recently, investigators have had great success using mathematical models to explore the relationship of structure to function in normal vascular beds. When investigators first explored how vascular beds adapt to set shear stress at appropriate levels, however, some vessels tended to regress, and some tended to grow into arteriovenous shunts. Degeneration of the arterial tree is prevented when flow regulation is added to the model. The present work explores the implication of this theoretical development and illustrates how it may explain the genesis of arteriovenous malformations (AVMs). We use a simple model to illustrate how impairing local control of blood flow causes models to become structurally unstable, yielding a structure and behavior similar to AVMs. This work shows how the lack of local flow control can be the cause, not just the result, of arteriovenous malformations. With insight gained from this modeling approach, specific, focused experiments can be designed. [Neurol Res 2001; 23: 641-644]

Balance point characterization of interstitial fluid volume regulation

The individual processes involved in interstitial fluid volume and protein regulation (microvascular filtration, lymphatic return, and interstitial storage) are relatively simple, yet their interaction is exceedingly complex. There is a notable lack of a first-order, algebraic formula that relates interstitial fluid pressure and protein to critical parameters commonly used to characterize the movement of interstitial fluid and protein. Therefore, the purpose of the present study is to develop a simple, transparent, and general algebraic approach that predicts interstitial fluid pressure (P(i)) and protein concentrations (C(i)) that takes into consideration all three processes. Eight standard equations characterizing fluid and protein flux were solved simultaneously to yield algebraic equations for P(i) and C(i) as functions of parameters characterizing microvascular, interstitial, and lymphatic function. Equilibrium values of P(i) and C(i) arise as balance points from the graphical intersection of transmicrovascular and lymph flows (analogous to Guytons classical cardiac output-venous return curves). This approach goes beyond describing interstitial fluid balance in terms of conservation of mass by introducing the concept of inflow and outflow resistances. Algebraic solutions demonstrate that P(i) and C(i) result from a ratio of the microvascular filtration coefficient (1/inflow resistance) and effective lymphatic resistance (outflow resistance), and P(i) is unaffected by interstitial compliance. These simple algebraic solutions predict P(i) and C(i) that are consistent with reported measurements. The present work therefore presents a simple, transparent, and general balance point characterization of interstitial fluid balance resulting from the interaction of microvascular, interstitial, and lymphatic function.

First-order approximation for the pressure-flow relationship of spontaneously contracting lymphangions

To return lymph to the great veins of the neck, it must be actively pumped against a pressure gradient. Mean lymph flow in a portion of a lymphatic network has been characterized by an empirical relationship (P(in) - P(out) = -P(p) + R(L)Q(L)), where P(in) - P(out) is the axial pressure gradient and Q(L) is mean lymph flow. R(L) and P(p) are empirical parameters characterizing the effective lymphatic resistance and pump pressure, respectively. The relation of these global empirical parameters to the properties of lymphangions, the segments of a lymphatic vessel bounded by valves, has been problematic. Lymphangions have a structure like blood vessels but cyclically contract like cardiac ventricles; they are characterized by a contraction frequency (f) and the slopes of the end-diastolic pressure-volume relationship [minimum value of resulting elastance (E(min))] and end-systolic pressure-volume relationship [maximum value of resulting elastance (E(max))]. Poiseuilles law provides a first-order approximation relating the pressure-flow relationship to the fundamental properties of a blood vessel. No analogous formula exists for a pumping lymphangion. We therefore derived an algebraic formula predicting lymphangion flow from fundamental physical principles and known lymphangion properties. Quantitative analysis revealed that lymph inertia and resistance to lymph flow are negligible and that lymphangions act like a series of interconnected ventricles. For a single lymphangion, P(p) = P(in) (E(max) - E(min))/E(min) and R(L) = E(max)/f. The formula was tested against a validated, realistic mathematical model of a lymphangion and found to be accurate. Predicted flows were within the range of flows measured in vitro. The present work therefore provides a general solution that makes it possible to relate fundamental lymphangion properties to lymphatic system function.

Adaptation of cerebral circulation to brain arteriovenous malformations increases feeding artery pressure and decreases regional hypotension.

PURPOSE To determine how the adaptation of extranidal cerebral vessels affects feeding artery pressure, draining vein pressure, and regional hypotension due to the presence of brain arteriovenous malformations (BAVMs). CONCEPT BAVMs cause high flows in feeding arteries and draining veins and can induce profound hypotension in the neighboring vasculature. Despite the large difference in flow, endothelial shear stress (&tgr;) observed in vessels ipsilateral to the BAVM is similar to &tgr; in vessels contralateral to the BAVM, suggesting that the conductance vessels successfully adapt to keep &tgr; constant. However, because BAVMs are discovered only after they are well developed, the natural history of the adaptation process in extranidal vessels is unknown. RATIONALE Currently, no way exists to determine experimentally the effects of adaptation of extranidal vessels in human patients. Therefore, a mathematical model of the cerebral vasculature is used to study adaptation in response to BAVMs. By comparing pressures and flows calculated before and after adaptation, the effect of adaptation of the conductance vessels on regional hemodynamics can be evaluated. DISCUSSION Structural adaptation of the extranidal circulation seems not only to reset &tgr;, but also to ameliorate regional hypotension induced by BAVMs. However, this compensatory mechanism also increases feeding artery pressure and thus may increase the risk of hemorrhagic stroke.

Lymphatic pump-conduit duality: contraction of postnodal lymphatic vessels inhibits passive flow

Lymphangions, the segments of lymphatic vessels between valves, exhibit structural characteristics in common with both ventricles and arteries. Although once viewed as passive conduits like arteries, it has become well established that lymphangions can actively pump lymph against an axial pressure gradient from low-pressure tissues to the great veins of the neck. A recently reported mathematical model, based on fundamental principles, predicted that lymphangions can transition from pump to conduit behavior when outlet pressure falls below inlet pressure. In this case, the axial pressure gradient becomes the major source of energy for the propulsion of lymph, despite the presence of cyclical contraction. In fact, flow is augmented when cyclical contractions are abolished. We therefore used an in vitro preparation to confirm these findings and to test the hypothesis that lymphangion contraction inhibits flow when outlet pressure falls below inlet pressure. Bovine postnodal mesenteric lymphatic vessels harvested from an abattoir were subjected to an inlet pressure of 5.0 cmH(2)O and an outlet pressure that decreased from 6.5 to 3.5 cmH(2)O under control conditions, stimulated with U-46619 (a thromboxane analog) and relaxed with calcium-free solution. Under control conditions, lymphatic flow markedly increased as outlet pressure fell below inlet pressure. In this case, the slopes of the flow versus axial pressure gradient increased with calcium-free conditions (61%, n = 8, P = 0.016) and decreased with U-46619 stimulation (21%, n = 5, P = 0.033). Our findings indicate that the stimulation of lymphatic contractility does indeed inhibit lymphatic flow when vessels act like conduits.

Adaptation of mesenteric lymphatic vessels to prolonged changes in transmural pressure

In vitro studies have revealed that acute increases in transmural pressure increase lymphatic vessel contractile function. However, adaptive responses to prolonged changes in transmural pressure in vivo have not been reported. Therefore, we developed a novel bovine mesenteric lymphatic partial constriction model to test the hypothesis that lymphatic vessels exposed to higher transmural pressures adapt functionally to become stronger pumps than vessels exposed to lower transmural pressures. Postnodal mesenteric lymphatic vessels were partially constricted for 3 days. On postoperative day 3, constricted vessels were isolated, and divided into upstream (UP) and downstream (DN) segment groups, and instrumented in an isolated bath. Although there were no differences between the passive diameters of the two groups, both diastolic diameter and systolic diameter were significantly larger in the UP group than in the DN group. The pump index of the UP group was also higher than that in the DN group. In conclusion, this is the first work to report how lymphatic vessels adapt to prolonged changes in transmural pressure in vivo. Our results suggest that vessel segments upstream of the constriction adapt to become both better fluid conduits and lymphatic pumps than downstream segments.