Structural Autoregulation Research Articles

Neuronal Apoptosis-inhibitory Protein Does Not Interact with Smac and Requires ATP to Bind Caspase-9

The neuronal apoptosis-inhibitory protein (NAIP) is the founding member of the mammalian family of inhibitor of apoptosis (IAP) proteins (also known as BIRC proteins) and has been shown to be antiapoptotic both in vivo and in vitro. The 160-kDa NAIP contains three distinct regions: an amino-terminal cluster of three baculoviral inhibitory repeat (BIR) domains, a central nucleotide binding oligomerization domain (NOD), and a carboxyl-terminal leucine-rich repeat (LRR) domain. The presence of the NOD and LRR domains renders NAIP unique among the IAPs and suggests that NAIP activity is regulated in a manner distinct from that of other members of the family. In this report, we examined the interaction of various regions of NAIP with caspase-9 and Smac. Recombinant NAIPs with truncations of the carboxyl-terminal LRR or NOD-LRR regions bound to caspase-9. In contrast, the full-length protein did not, suggesting some form of structural autoregulation. However, the association of the wild type full-length protein with caspase-9 was observed when interaction analysis was performed in the presence of ATP. Furthermore, mutation of the NAIP ATP binding pocket allowed full-length protein to interact with caspase-9. Thus, we conclude that NAIP binds to caspase-9 with a structural requirement for ATP and that in the absence of ATP the LRR domain negatively regulates the caspase-9-inhibiting activity of the BIR domains. Interestingly, and in contrast to the X-chromosome-linked inhibitor of apoptosis protein (XIAP), NAIP-mediated inhibition of caspase-9 was not countered by a peptide containing an amino-terminal IAP binding motif (IBM). Consistent with this observation was the failure of Smac protein to interact with the NAIP BIR domains. These results demonstrate that NAIP is distinct from the other IAPs, both in demonstrating a ligand-dependent caspase-9 interaction and in demonstrating a distinct mechanism of inhibition.

Structural adaptation of vascular networks: role of the pressure response.

Structural reductions in vessel luminal diameters in response to elevated pressure may play a role in the elevation of peripheral resistance generally observed in hypertension. In the present study, a theoretical model is used to simulate the effect of increased driving pressure on flow resistance in microvascular networks. The angioarchitecture (lengths and diameters of all segments, topology) of microvascular networks (n=6) in the rat mesentery was recorded by intravital microscopy. The model simulation of vascular adaptation in response to local wall shear stress, transmural pressure, and tissue PO(2) was used to predict changes in network pressure drop and flow resistance for a given change of driving pressure (DeltaP). For DeltaP increasing from 15% to 190% of the normotensive value, a 3.3-fold increase in flow resistance was observed (structural autoregulation). If vascular reactivity to pressure was suppressed, the resistance increase was abolished. Suppressing pressure sensitivity also led to a rise in mean capillary pressure at normal driving pressure from 23.8+/-7.3 mm Hg to 34+/-6.9 mm Hg. These results indicate that low capillary pressure levels as well as structural autoregulation depend on vascular responses to circumferential wall stress (corresponding to pressure). This tendency of peripheral vascular beds to increase flow resistance for a given increase of bulk flow or driving pressure may amplify and stabilize blood pressure elevation in the development of hypertension.

Altered myogenic responsiveness of the renal microvasculature in experimental hypertension.

Recent investigations have delineated the renal microvascular responsiveness to pressure, by using isolated afferent arterioles, juxtamedullary nephrons, and isolated perfused hydronephrotic kidneys. Both afferent arterioles and interlobular arteries (ILA) manifest pressure-dependent vasoconstrictor responses to elevated renal arterial pressure. Several recent studies have indicated that the afferent arteriole adjacent to the glomerulus constricts primarily in response to tubuloglomerular feedback signals, whereas the afferent arteriole near the ILA is under the dominant influence of myogenic tone. Furthermore, the responsiveness of the ILA to pressure is dependent on the basal diameter, with the smaller diameter (distal) segments demonstrating more marked responses than do the larger (proximal) segments. The myogenic afferent arteriolar response is shifted to higher perfusion pressure in spontaneously hypertensive rat (SHR) kidneys, and blunted both in Dahl salt-sensitive rats and in Goldblatt renal hypertensive rats. This altered responsiveness of the afferent arteriole may account for the alterations in renal blood flow autoregulation, namely, resetting toward higher pressures in SHR, and impairment in Dahl salt-sensitive rats and Goldblatt hypertensive rats Distal ILA segments vasoconstricted similarly in response to pressure both in SHR and in Wistar-Kyoto rats (WKY), whereas proximal ILA segments did not exhibit vasoconstriction in either strain. The intermediate ILA segment from SHR kidneys manifests more prominent myogenic vasoconstriction than does that from WKY rat kidneys. The enhanced myogenic responsiveness of the intermediate ILA segment may act in concert with afferent arteriolar vasoconstriction to prevent glomerular hypertension in superficial nephrons. Finally, the myogenic vasoconstriction of renal microvessels is mediated in part by voltage-dependent calcium channels, and the altered myogenic response may be associated with modified activity of voltage-dependent calcium channels. Thus, the myogenic preglomerular tone constitutes a pivotal determinant of renal autoregulation, and teleologically may also play an important role in protecting glomeruli from barotrauma in hypertension, whereas the functional myogenic element is soon reinforced by an element of "structural autoregulation' of preglomerular resistance vessels.

Nephrosclerosis from childhood to old age, a viewpoint

Cortical arteries of the kidney in benign nephrosclerosis are characterized by arterial intimal fibroplasia whereas arterioles are affected by hyalinization; these features overlap in the tiniest terminal arteries. In malignant nephrosclerosis, the characteristic lesions are mucoid edema and fibrinoid necrosis respectively. A fifth kind of vasculopathy is marked by reduced calibre and increased wall thickness to diameter ratio; although this is often called “hypertrophy”, wall mass may not be increased, and the name “structural autoregulation” has been proposed in its place. Fibroplasia is found to some degree in every elderly person, even those who never experienced high blood pressure; blood pressure is elevated in those who manifest more than what is usual for the age. A review of reports concerning hypertension in subjects who lack evidence of nephrosclerosis suggests that such subjects may be statistical outliers who are likely to demonstrate regression to the mean in blood pressure rather than subsequent progression of renovasculopathies. It is proposed that uneven sclerosis of arteries may cause heterogeneity of nephrons so that some nephrons are sufficiently ischemic to evoke elevation of blood pressure by Goldblatt mechanisms, while other nephrons have structural autoregulation. A kidney with a small population of ischemic nephrons may show normal overall average function by available clinical methods. The etiology of arterial intimal fibroplasia in aging normotensives is unknown. That unknown etiology could, in theory, explain hypertension as merely the consequence of the more extreme degrees of benign renovasculopathies. A novel kind of epidemiological approach is proposed for pursuing clues to the unknown etiology.

Structure and function of the arteries in hypertension

Like tissues in other parts of the body, those of the heart and blood vessels can rapidly adapt their design. The principles of these differentiated structural changes in response to altered functional demands will be outlined in this report. With respect to arterial resistance vessels in hypertension, any sustained arterial pressure elevation leads to wall ( w) hypertrophy, whereas the average inner radius ( r i ) decreases. The reverse occurs at sustained pressure reductions, and this process is aptly termed “structural autoregulation.” By means of this structural autoregulation, wall tension per unit layer ( T) remains largely constant when pressure ( P) increases (decreases), according to Laplace's law: T = P × r w . Furthermore, this structural w r i increase, because it is a local vascular response although it is often considerably modified by neurohormonal “trophic” influences, results in a geometrically based vascular hyperreactivity affecting the systemic precapillary resistance vessels, whereas the structural r i reduction leads to an upward resetting of systemic resistance to flow which is present even at maximal vasodilatation ( Rmin). Because of this “structural amplifier” principle, an increased systemic resistance can be maintained even at normal vascular smooth muscle activity, and smooth muscle activations may then lead to exaggerated resistance elevations. Thus, a most important positive-feedback interaction is created between even mild functional “pressor” influences, if adequately sustained, and this normal process of structural adaptation. This positive-feedback interaction therefore gradually tends to accentuate the latter element until it entirely dominates the hemodynamics of established hypertension. As the process is induced early and established rapidly, and in primary hypertension often even seems to be genetically reinforced in various ways, it becomes of utmost pathogenetic significance. With respect to the aorta-large conduit arteries, their “Windkessel function” becomes reduced by the same process of adaptive wall thickening. This increases the pulse amplitude and thereby accentuates the systolic afterload of the left heart, the load of which is raised also because of the upward structural resetting of systemic precapillary resistance. Furthermore, the same type of structural adaptation also contributes to the upward resetting of the cardiac, arterial, and renal “barostat” mechanisms, as cardiac and arterial walls become thicker and stiffer, whereas renal preglomerular resistance vessels participate in the upward structural autoregulation. Finally, in view of this general background, antihypertensive treatment should be increasingly directed toward regression of the upward cardiovascular structural adaptation, not only to reduce the pressure load, per se, but also to counteract more specifically various “trophic” influences that appear to be quite significant. However, even if intense treatment of primary hypertension could induce full structural normalization, it is unlikely that all subsequent treatment could be abandoned, simply because various genetic predisposing factors still exist, which could trigger a recurrence.

Vascular Changes in Hypertension

A review of the general nature of cardiovascular structural adaptation and how this per se normal process becomes of key haemodynamic importance for the development of primary hypertension, particularly with respect to the gradual elevation of systemic precapillary resistance is presented. Because of the structural 'upward resetting' of the haemodynamic equilibrium, antihypertensive therapy in reality faces a far more formidable task in chronic hypertension than merely 'normalising' a supposedly raised vascular smooth muscle activity or/and cardiac output. Rather, it must bring about sub-normal activity levels to normalise the arterial pressure level, and only when such a pressure lowering has been sustained enough to allow for structural regression towards normal dimensions is a true normalisation achieved. However, the process of structural regression takes time and is complicated by the fact that the often long duration of the high-pressure state has led to structural changes which can be quite difficult to reverse. Finally, physiological-haemodynamic reasons are discussed which direct pharmacological interferences preferentially towards the pronounced myogenic activity of the precapillary resistance vessels, which both in normo- and hypertension is by far the most dominating element behind resting smooth muscle activity in these vessels and is, moreover, especially dependent on influx of external calcium ions. As the raised precapillary resistance (by means of 'structural autoregulation') represents the key element behind the pressure rise in established hypertension, such a pharmacological interference is directed towards the proper haemodynamic site and would not directly interfere with the neurohormonal integrative control of the circulation.

Brief historical background and principal nature of process.

After a brief outline of the historical background, the biological principle of structural tissue adaptation to alterations in load is discussed with special reference to the cardiovascular system. It is stressed that adaptive changes of cardiac and vascular design to local load are rapid, precise, and, on the local level, highly appropriate. However, in hypertension, when they affect the entire systemic resistance section (structural autoregulation), as well as some major "barostats," an upward structural resetting of the entire pressure equilibrium occurs. Further, by way of the consequent vascular resistance vessel hyperreactivity, a positive feedback interaction is established with functional pressure effects and thus tends to further escalate the pressure rise. For these reasons the "normal" structural factor becomes of key importance for the initiation, maintenance, and gradual aggravation of chronic high pressure states.

Structural changes of large arteries in sustained essential hypertension.

The physical properties of intact superficial arteries can be studied in humans by using original pulsed Doppler systems. Measurements of the diameter, blood flow velocity, volumic flow, and compliance of the brachial artery can be obtained in hypertensive humans in comparison with controls of the same age. In sustained essential hypertension, arterial compliance is decreased, in a manner that is not related exclusively to age and to the level of blood pressure. On the basis of pharmacological studies, the predominant role of activation of the autonomic nervous system can be excluded. As observed in isolated systolic hypertension and in arteriosclerosis obliterans of the lower limbs, the reduction in arterial compliance is probably due to structural alterations of the arterial wall, which produce a disproportionate increase in systolic pressure. Nitroglycerine is able to reverse both the decreased compliance and the increased systolic pressure. The conclusion follows that adaptive changes of large arteries participate in the structural autoregulation of blood flow in hypertension and lead to a predominant elevation of systolic pressure in older subjects.

Cardiovascular studies in rats with respect to some functional and structural relationships of relevance in hypertension and ordinary aging.

Five current lines of cardiovascular studies in rats are outlined, mainly dealing with some functional and structural relationships of particular relevance for hypertension and ordinary aging: 1. Characteristics of the smooth muscles and their neurogenic control in 'Windkessel' arteries, conduit arteries, precapillary resistance vessels and venous capacitance vessels from normotensive rats (WKY) with comparisons to rats with primary hypertension (SHR). 2. Different types of structural renovascular adaptation, comparing aging with advancing SHR hypertension, with 'high-pressure' and 'low-pressure' kidneys in one-clip, two-kidney renal hypertension, and with hypertrophied kidneys in uni-nephrectomized normotensive rats. 3. Relationships between 'structural autoregulation', wall distensibility, vascular reactivity and smooth muscle sensitivity in SHR and WKY hindquarter resistance vessels along with aging. 4. Relationships between wall thickness, luminal dimension and contractility in left ventricles from SHR and WKY during aging, and when one-clip, two-kidney hypertension is superimposed. 5. Interference with the capacity of the neurohormonal mechanisms counteracting blood loss in rats when on chronic low-salt diet.

Structural factors: the vascular wall. Consequences of treatment.

Like all tissues, blood vessels readily adapt their structure upon sustained functional changes. For example, pressure increases soon induce a largely proportional wall (w) thickening, where arteries, veins, and true resistance vessels respond alike. The latter also show a modest structural narrowing of average inner radius (ri), where the increased w/ri ratio results in a geometrically based vascular hyperreactivity. In primary hypertension, this type of precapillary resistance vessel adaptation implies an important "upward structural autoregulation" of systemic resistance, which is thereby kept increased also when vascular smooth muscle activity is entirely normal. Further, the systemic vascular hyperreactivity introduces a positive feedback interaction with functional pressor influences. By this mechanism, even marginal increases in "functional drive" may, if only sustained, steadily enhance the structural w/ri increase until it dominates hemodynamics. Similar alterations of the renal preglomerular vessels cause an early upward resetting of the renal barostat function, while wall thickening of large arteries helps to reset the baroreflexes. Also, the capacitance vessels show some structural adaptation that reduces venous compliance and contributes to blood volume centralization. Due to this overall structural resetting of hypertensive cardiovascular systems, the pharmacological problem of normalizing blood pressure is not one of merely damping an increased vascular smooth muscle activity. The task is more formidable, because effector cell activity must be kept even subnormal, despite counterregulatory mechanisms. These mechanisms almost all have been redesigned to maintain the high pressure state, with the long-range goal that true regression toward normality should ultimately ensue.

Structurally based changes of renal vascular reactivity in spontaneously hypertensive and two-kidney, one-clip renal hypertensive rats, as compared with kidneys from uninephrectomized and intact normotensive rats.

Renal vascular beds from spontaneously hypertensive rats (SHR) at different stages of hypertension, from two-kidney, one-clip renal hypertensive rats (RHR) and from uninephrectomized rats (UNR) were in constant-flow, paired perfusions compared with kidneys from normotensive control rats (NCR) concerning vascular smooth muscle sensitivity to noradrenaline (NA) and resistance vessel reactivity, as reflected by the position, respectively the shape, of the dose-resistance response curves. None of these kidney variants differed significantly from controls concerning smooth muscle sensitivity to NA during in vitro perfusion. However, both the steepness and maximal pressor responses of the renal resistance curves increased progressively with age in SHR, to become ultimately much enhanced when related to age-matched controls. It suggests a well preserved smooth muscle contractility and a progressive elevation of the average wall/lumen ratio in the SHR renal resistance vessels. Also the untouched, "high-pressure" RHR kidneys showed increased vascular reactivity, while it was somewhat reduced in the clipped, "low-pressure" RHR kidneys and unchanged in the hypertrophied but normotensive UNR kidneys. These results, when combined with other findings concerning renal vascular design (Göthberg & Folkow 1982a), illustrate how the renal resistance vessels readily adapt structurally to hypertension, hypotension, kidney hypertrophy and also with age, and in directions which tend to chronically "autoregulate" glomerular blood supply and filtration.

'Structural autoregulation'--the local adaptation of vascular beds to chronic changes in pressure.

Blood vessels readily adapt their design in response to sustained functional changes. If pressure (P) increases, the resulting thickening of the walls (w) of the resistance vessels, associated with a reduction in average inner radius (ri), keeps wall tension per unit wall layer (T) constant, because the increased w/ri ratio largely balances the raised pressure (Laplace's law: T = P X ri/w). The opposite occurs when there are sustained reductions in pressure. This locally elicited, mainly precapillary structural adaptation is a long-range equivalent to precapillary functional autoregulation and deserves to be called structural autoregulation. In primary hypertension there is an early 'structural resetting' of the systemic precapillary resistance, due to narrowing of ri and to vascular hyperreactivity ensuing from the increase in w/ri. These structural changes imply an increased resistance to flow at normal levels of vascular smooth muscle activity. Furthermore, even mild functional pressor influences will, if sustained, by a positive feedback interaction with the initially mild vascular hyperreactivity gradually accentuate the structural increase in w/ri. Marked rises in pressure may ensue from this interaction, implying that it is a major causative element in primary hypertension. As the renal preglomerular resistance vessels are similarly structurally autoregulated, this implies an early largely parallel resetting of the important renal 'long-term barostat function'. Further, as the walls of large arteries get thicker and stiffer, this helps to reset the baroreceptors. Finally, as the venous capacitance vessels adapt in a similar way the slight rise in average venous pressure in primary hypertension will reduce venous compliance, which helps to 'centralize' the usually slightly reduced blood volume.

‘Structural Autoregulation’ of the Preglomerular/Postglomerular Resistance Ratio and Hence of Glomerular Filtration Rate in the Clipped (Low Pressure) Kidney in Two-Kidney, One-Clip Renal Hypertension

1. The chronically clipped left kidneys of two-kidney, one-clip renal hypertensive rats (duration >4 weeks) showed a 45% decrease in organ weight compared with left kidneys from age-matched normotensive Wistar rats (0.59 ± 0.09 vs 1.12 ± 0.05 g). 2. These ‘low-pressure’ kidneys exhibited at maximal vasodilatation a 40% decrease in total renal vascular resistance per unit kidney weight, a reduction in the preglomerular/postglomerular resistance ratio (filtration curve displaced markedly to the left of the control), though combined with some decrease in maximal glomerular filtration capacity. 3. Thus the vascular bed of chronically clipped low-pressure kidneys displays a ‘downward’ structural autoregulation, which by lowering of the total renal vascular resistance and the preglomerular/postglomerular resistance ratio serves to maintain blood flow and to increase filtration pressure thereby raising the filtration fraction.

Vascular resistance and reactivity of the microcirculation in hypertension.

This brief review summarizes the author’s current understanding of the circulatory changes in hypertension. Differences in four important regulatory systems are dependent on structural changes: (1) An increase in wall-to-lumen ratio of precapillary resistance vessels is responsible for an increase in vascular reactivity, or ‘structural autoregulation’. (2) A structural change primarily in the preglomerular arteriole causes a resetting of the pressure required for glomerular filtration. This serves a ‘long-tem barostatic function’. (3) Stiffening of the aorta and other pressure-sensing systems contributes to a resetting of baroreceptors bringing about a reset of the ‘short-term barostats’. (4) Left ventricular hypertrophy causes a decrease in compliance, hence tending to decrease stroke volume for a given filling pressure. Functional changes such as increased neurogenic activity may serve as important ‘trigger’ elements in spontaneously hypertensive rats and at least in one important variant of essential hypertension in the human. An example of a functional alteration in vascular smooth muscle is found in that the vascular resistance response in the spontaneously hypertensive rat in low calcium concentration (0.2 mM) is better maintained than in the normotensive control rat, but this alteration seems to be secondary in nature. An experiment is described which permits simultaneous assessment of the responses of capacitance and resistance vessels to nerve stimulation: when the splanchnic nerves are stimulated there is a simultaneous decrease in venous capacity and an increase in resistance in the liver, gastrointestinal tract and kidneys. The decrease in venous capacity is reflected in an increase in stroke volume whereas the increase in regional resistance is evidenced in an incraese in total peripheral resistance. Using this index the spontaneously hypertensive rats had a less efficient capacitance response (possibly due to the decrease in ventricular compliance) and a greater resistance response than did the normotensive control rat. Although both functional and structural changes in the cardiovascular system occur, the rapidly developed structural changes appear to be the major determinant of the differences between normal and hypertensive hemodynamics.

Structural “Resetting” of the Renal Vascular Bed in Spontaneously Hypertensive Rats (SHR)

Studies in both man and rats (cf. Folkow et al. 1973, 1974) show that a rapid structural adaptation occurs early in hypertension which, besides the left heart and systemic arteries, affects the precapillary resistance vessels in a hemodynamically most important way. Here a wall (mainly media) thickening takes place which tends to encroach upon the inner radius, thus raising the w/ri ratio. The rapidity, generalization and extent of this precapillary ‘“structural autoregulation” to average changes in pressure load makes it crucial both for the initiation and maintenance of a chronic high‐pressure state, whichever the initiating elements are. The same principle of hypertrophic adaptation in the left heart and large arteries leads to a functionally important displacement of the “Starling curve” towards the right (Hallbäck, Isaksson and Noresson 1975) and to baroreceptor resetting (e.g. Jones 1977).

Role of the vascular factor in hypertension.

A survey is given of experimental results in both man and hypertensive rats, suggesting a rapid and hemodynamically important structural 'resetting' of the systemic precapillary resistance vessels, of the renal 'long-term' and carotid-aortic 'short-term barostats', as well as of the left heart, which together greatly affect both the initiation and maintenance of hypertension. Particularly the adaptation in design of the precapillary resistance vessels, being a per se normal, local response to more sustained changes in transmural pressure ('structural autoregulation'), implies the introduction of a potential vicious circuit once it affects the entire vascular bed. The reason is that this type of altered vessel design leads to a systemic precapillary hyperreactivity that forms a positive feedback interaction with functional excitatory influences as far as their long range, hemodynamic effect on the arterial pressure level is concerned. It is further discussed how various types of structural and functional vascular changes may often coexist, then mutually interacting with each other, and how they may be experimentally separated for detailed analysis.

Consequences of myocardial structural adaptation on left ventricular compliance and the Frank-Starling relationship in spontaneously hypertensive rats.

The Frank-Starling relationship of hearts from adult spontaneously hypertensive rats (SHR, Okamoto 1969), representing the established phase of hypertension, and of young SHR, representing the initial phase of hypertension, was investigated by using the isolated working heart preparation. In the "normal" diastolic pressure range (5 to 10 cm H2O), the left ventricle of both SHR groups displayed significantly reduced stroke volumes compared with hearts of normotensive controls (NCR); the degree of reduction being proportional to the left ventricular hypertrophy. This is suggested to be due to a reduced left ventricular diastolic compliance in SHR, as indicated by direct measurements of ventricular wall thickness and end-diastolic volumes in arrested hearts exposed to different end-diastolic filling pressures. Such a progressive shift of the Frank-Starling relationship to the right with duration of hypertension could, in combination with the gradual development of "structural autoregulation" of the precapillary resistance vessels, constitute dominating factors in shifting the hemodynamic situation in labile hypertension into that characterizing the established, or "fixed", state of hypertension.