Ashley S. Izzard

Vascular Structural and Functional Changes in Type 2 Diabetes Mellitus Evidence for the Roles of Abnormal Myogenic Responsiveness and Dyslipidemia

Background—To further investigate vascular morphology and function in type 2 (non–insulin-dependent) diabetes mellitus (type 2D), small arteries were examined in vitro from carefully defined cohorts of patients with or without concomitant hypertension and the results compared with those from selected normotensive nondiabetic control subjects and a group of untreated patients with essential hypertension (EH). Methods and Results—Blood vessels were studied through the use of pressure myography to determine vascular morphology, mechanics, and myogenic responsiveness, together with testing of constrictor and dilator function. Small arteries from patients with EH demonstrated eutrophic inward remodeling and an increased distensibility. Vessels from type 2D patients demonstrated hypertrophy, a further increase in distensibility, and a highly significant loss of myogenic responsiveness compared with patients with EH and control patients. Vasoconstrictor function to norepinephrine was normal in patients with type 2D and type 2D+H and EH. Endothelium-dependent dilation was normal in patients with EH but abnormal in patients with type 2D and type 2D+H. There was a significant correlation between dilator impairment and the degree of dyslipidemia recorded in all groups. Conclusions—These results demonstrate vascular hypertrophy in small arteries from patients with type 2D. This could be a consequence of impaired myogenic responsiveness, which will increase wall stress for a given intraluminal pressure, which may be a stimulus for vascular hypertrophy. A substantial proportion of endothelial dysfunction can be attributed to an effect of the abnormal lipid profile seen in such patients.

Small artery structure and hypertension: Adaptive changes and target organ damage

Hypertension is known to be associated with an increase in the wall/lumen ratio (W/L) of the resistance arteries. Growth, eutrophic remodelling and changes in arterial distensibility can all contribute to an increase W/L. Wall stress may stimulate growth, whereas remodelling and/or reduced distensibility may be the result of prolonged contraction. Impaired or overwhelmed pressure-induced myogenic constriction, causing increased wall stress, may explain the small artery growth seen in diabetes and secondary hypertension, respectively. We find that small artery growth is a greater predictor of cardiovascular events than an increased W/L.

Effects of Angiotensin Type-1 Receptor Antagonism on Small Artery Function in Patients With Type 2 Diabetes Mellitus

Endothelial dysfunction has been demonstrated to occur in small arteries from patients with type 2 diabetes and hypertension. The effects of angiotensin II receptor blockade on vessel function were examined using pressure myography in a randomized 12-week double-blind placebo-controlled parallel group study using candesartan cilexitil. The maximal vascular response to acetylcholine (Ach) was impaired at baseline and improved with candesartan. This improvement was primarily caused by an effect in the nitric oxide component of Ach-mediated dilatation. The degree of endothelial dysfunction directly correlated with serum low-density lipoprotein cholesterol levels. Sodium nitroprusside-induced endothelium-independent dilatation was reduced in diabetic patients and intervention with candesartan lead to an improvement in EC50 with no change in maximal response. Vasoconstriction to norepinephrine was normal and did not change with intervention, but responses to angiotensin II were reduced after candesartan in diabetic patients. These results demonstrate that even brief treatment with angiotensin II receptor blockade is associated with a significant improvement in resistance vessel endothelial function.

Small artery structure and function in hypertension

•  Introduction •  Structural changes in the circulation •  Remodelling and hypertrophy in the circulation •  Molecular mechanisms responsible for eutrophic remodelling •  Small artery function •  Conclusions

Hypertension and the vasculature : arterioles and the myogenic response

Objective This editorial was invited by the Journal of Hypertension as one of a series designed to examine our current knowledge of several aspects of the pathophysiology of hypertension. This article considers small arteries and arterioles. Setting The conclusion that established hypertension is characterized by a normal cardiac output and a raised peripheral resistance represents the integration of findings from haemodynamic studies using a variety of models of the disease examined by several different techniques. In some ways it assumes that all vascular beds conform to the same pattern of responsiveness. However, given the obvious heterogeneity of functions performed by specialized tissues, the recognized variations in receptor populations and the differences in innervation found in the vascular wall throughout the circulation, this might not be the case. Resistance to blood flow occurs throughout the vascular tree, but the majority is found at the level of arterioles. Upstream small arteries demonstrate growth and remodelling changes which result in luminal narrowing, but the exact contribution of such vessels to resistance is still not known. Perhaps the most interesting recent finding in this context is that blood pressure can fall immediately after a pressor stimulus has been removed, despite the demonstration of such structural changes in small arteries. Furthermore, some whole-animal studies have been reported which fail to show the expected vascular amplification when the circulation is stressed in total. Conclusion Viewing the vascular tree as an integrated circuit with specialized functions when nourishing specific tissues suggests that when the resistance in one vascular bed increases because of a constrictor challenge, this might not be representative of the circulation as a whole: indeed, resistance may fall elsewhere. It is probable that structural changes in small arteries represent the consequence of hypertension. The pathogenesis of hypertension may reside downstream in arterioles, where a myogenic response might play a fundamental role.

Middle cerebral artery structure and distensibility during developing and established phases of hypertension in the spontaneously hypertensive rat.

Objective The aims of the current study were to examine the structural properties of middle cerebral arteries (MCA) from young (5–7 weeks) and adult (20–24 weeks) spontaneously hypertensive rats (SHR), compared with age-matched Wistar–Kyoto (WKY) control rats. Design MCA segments (8–10 per group) were secured onto glass pipettes in a small vessel chamber and studied using a pressure arteriograph system. Vessels were perfused in Ca2+-free physiological salt solution to ensure the absence of tone. The wall thickness and lumen diameter were recorded at intraluminal pressures ranging from 3 to 180 mmHg using a video dimension analyser. Results There was a borderline increase in systolic pressure of the young SHR, compared with WKY controls, but the systolic pressure of the older SHR was significantly raised. The MCA lumen diameter from young SHR was reduced across the entire pressure range and arterial distensibility was not reduced, compared with WKY vessels. The MCA lumen diameter from adult SHR was reduced at high pressure, but converged with the lumen diameter of the WKY vessels at 3 mmHg, and the stress–strain relation was shifted to the left, compared with the WKY vessels; nevertheless, the slope of the tangential elastic modulus–stress relation was not significantly increased. The pressure–wall cross-sectional area relationship did not differ between strains at either time point. Conclusions These data demonstrate eutrophic inward remodelling of the MCA from young SHR, compared with WKY controls. In the adult SHR the structural changes are probably a consequence of a reduced arterial distensibility.

Myogenic Tone in Coronary Arteries from Spontaneously Hypertensive Rats

The aims of this study were to investigate myogenic tone in cannulated coronary arteries from SHR (spontaneously hypertensive rats) and WKY (Wistar-Kyoto rats) at 5 and 20 weeks of age under pressurised no-flow conditions. Pressure-diameter relationships (20-200 mm Hg) were determined in the presence (active) and absence (passive) of calcium and myogenic tone at each pressure was calculated. Active, but not passive diameter-pressure relationships were significantly different between strains at both ages. Active diameters were similar between strains at pressures up to 140 mm Hg at 5 and 20 weeks. At higher pressures SHR arteries generated more tone. Maximum myogenic tone was similar between strains in spite of increased wall thickness in the SHR at both ages. Endothelium denudation increased myogenic tone to a greater extent in the SHR at both ages. Active diameters of endothelium-denuded SHR arteries were smaller than those of WKY in the range 20-120 mm Hg at 5 week and 20-80 and 160-180 mm Hg at 20 weeks. These results demonstrate that during both the developmental and established phases of hypertension, myogenic tone is not enhanced in intact SHR coronary arteries, except at the highest pressures. Following endothelium removal SHR arteries generated greater myogenic tone also at lower pressures. These data demonstrate a greater endothelium-mediated antagonism of myogenic tone in SHR coronary arteries.

Increased Wall-Lumen Ratio of Mesenteric Vessels From the Spontaneously Hypertensive Rat Is Not Associated With Increased Contractility Under Isobaric Conditions

We investigated the morphological (wall-lumen ratio) and contractile characteristics of distal mesenteric arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls at a distending pressure of 63% of the mean aortic pressure of each rat using a pressure arteriograph. The wall-lumen ratios obtained were compared with those obtained at a pressure of 100 mm Hg. Experiments were carried out at 5 and 20 weeks. Mean aortic pressure of SHR was significantly increased at 5 weeks compared with that of WKY and was further increased by 20 weeks. At 63% of mean aortic pressure, no difference in the wall-lumen ratio of the arteries was observed between strains at 5 weeks; at 20 weeks, the wall-lumen ratio of SHR arteries was significantly increased compared that in WKY arteries. The wall-lumen ratio of SHR vessels did not differ at 63% mean aortic pressure compared with 100 mm Hg at either 5 or 20 weeks, whereas this parameter was significantly reduced in WKY vessels at 100 mm Hg compared with 63% mean aortic pressure at 5 and 20 weeks. In the presence of spontaneous myogenic tone, there was a borderline reduction in the lumen diameter of SHR vessels compared with WKY vessels and with increasing norepinephrine concentrations at 5 weeks. At 20 weeks, lumen diameter between strains did not differ in the presence of myogenic tone nor with increasing norepinephrine concentrations. Similar results were obtained when vessels from both rat strains were pressurized to 80 mm Hg. Thus, the increased wall-lumen ratio in the distal mesenteric arteries from adult SHR compared with those from WKY is not associated with an increased contractility under isobaric conditions when studied at physiological distending pressure.

Impaired flow‐dependent dilatation in distal mesenteric arteries from the spontaneously hypertensive rat

1 The aim of the study was to examine the hypothesis that flow‐dependent dilatation is impaired in distal mesenteric arteries from adult spontaneously hypertensive rats (SHR) compared with normotensive Wistar‐Kyoto rat (WKY) controls and to assess the role of nitric oxide (NO). 2 Arterial segments were cannulated, pressurized to 80 mmHg and allowed to develop spontaneous myogenic tone. Flow was increased incrementally in vessels from both strains and responses were also assessed before and after incubation with the NO synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME). Responses to flow in control vessels were also assessed before and after intraluminal perfusion with antibody‐complement to disrupt the endothelium. 3 At a flow rate of 5 μl min−1, arteries from the WKY dilated significantly (22 ± 5 %, P< 0·01, n= 29) compared with the diameter at zero flow, whereas arteries from the SHR did not (4 ± 4 %, n.s., n= 16). Incubation with L‐NAME had no inhibitory effect on the responses to flow in either rat strain. In control arteries, antibody‐complement treatment abolished the dilatation in response to both flow and acetylcholine (ACh, 1 μM). 4 We conclude that flow‐dependent dilatation is impaired in distal mesenteric arteries from adult SHR compared with WKY controls. Furthermore, flow‐dependent dilatation is endothelium dependent, but L‐NAME insensitive, thus excluding the NO pathway in this abnormality. Impaired flow‐dependent dilatation may contribute to the increased peripheral resistance in hypertension.

Small Vessel Remodeling and Impaired Endothelial-Dependent Dilatation in Subcutaneous Resistance Arteries from Patients with Acromegaly

CONTEXT Patients with acromegaly have increased morbidity and mortality, predominantly from cardiovascular disease. Hypertension and diabetes are more prevalent, and both cause small vessel remodeling and endothelial dysfunction. OBJECTIVE To understand the structure and function of small arteries in acromegaly, sc blood vessels from gluteal fat biopsies were harvested from 18 patients with active disease (AD; age, 56 +/- 15 yr; 14 males), 23 patients in remission (CD; age, 55 +/- 12 yr; 15 males), and 20 healthy controls (age, 55 +/- 11 yr; 10 males) and examined in vitro using pressure myography. DESIGN Contractile responses to cumulative noradrenaline concentrations were recorded and followed by dose-dependent dilator responses to acetylcholine. The acetylcholine protocol was repeated after incubation with a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester) and cyclooxygenase inhibitor (indomethacin). After perfusion with Ca(2+)-free physiological saline solution, structural measurements were recorded at varying intraluminal pressures (3-180 mm Hg). RESULTS Wall thickness and wall:lumen ratio were increased in AD, reduced with treatment but remained greater in CD than controls. Wall cross-sectional area was increased in AD vs. controls (P < 0.001), decreased with treatment (AD vs. CD, P < 0.001), but remained higher than controls (CD vs. controls, P = 0.015). Growth index was increased in AD (20%) compared to controls (CD, 9%). Contractility was similar in all groups. Endothelial-dependent dysfunction was evident in AD compared with CD (P < 0.001) and controls (P < 0.01). Dilation did not change after N-nitro-L-arginine methyl ester but was impaired after indomethacin incubation. CONCLUSION Active acromegaly is associated with hypertrophic remodeling of the vascular wall and embarrassed endothelial function due to reduced nitric oxide and endothelium-derived hyperpolarizing factor bioavailability, both of which may contribute to the early mortality from cardiovascular disease.