Progressive vascular remodelling, endothelial dysfunction and stiffness in mesenteric resistance arteries in a rodent model of chronic kidney disease (original) (raw)
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Abnormalities associated with progressive aortic vascular dysfunction in chronic kidney disease
Frontiers in Physiology, 2015
Increased stiffness of large arteries in chronic kidney disease (CKD) has significant clinical implications. This study investigates the temporal development of thoracic aortic dysfunction in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Animals aged 12 and 18 weeks were studied alongside age-matched Lewis controls (total n = 94). LPK rodents had elevated systolic blood pressure, left ventricular hypertrophy and progressively higher plasma creatinine and urea. Relative to Lewis controls, LPK exhibited reduced maximum aortic vasoconstriction (R max ) to noradrenaline at 12 and 18 weeks, and to K + (12 weeks). Sensitivity to noradrenaline was greater in 18-week-old LPK vs. age matched Lewis (effective concentration 50%: 24 × 10 −9 ± 78 × 10 −10 vs. 19 × 10 −8 ± 49 × 10 −9 , P < 0.05). Endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation was diminished in LPK, declining with age (12 vs. 18 weeks R max : 80 ± 8% vs. 57 ± 9% and 92 ± 6% vs. 70 ± 9%, P < 0.05, respectively) in parallel with the decline in renal function. L-Arginine restored endothelial function in LPK, and L-NAME blunted acetylcholine relaxation in all groups. Impaired nitric oxide synthase (NOS) activity was recovered with L-Arginine plus L-NAME in 12, but not 18-week-old LPK. Aortic calcification was increased in LPK rats, as was collagen I/III, fibronectin and NADPH-oxidase subunit p47 (phox) mRNAs. Overall, our observations indicate that the vascular abnormalities associated with CKD are progressive in nature, being characterized by impaired vascular contraction and relaxation responses, concurrent with the development of endothelial dysfunction, which is likely driven by evolving deficits in NO signaling.
American Journal of …, 2011
Ng K, Hildreth CM, Phillips JK, Avolio AP. Aortic stiffness is associated with vascular calcification and remodeling in a chronic kidney disease rat model. Increased aortic pulse-wave velocity (PWV) reflects increased arterial stiffness and is a strong predictor of cardiovascular risk in chronic kidney disease (CKD). We examined functional and structural correlations among PWV, aortic calcification, and vascular remodeling in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Hemodynamic parameters and beat-to-beat aortic PWV were recorded in urethane-anesthetized animals [12-wk-old hypertensive female LPK rats (n ϭ 5)] before the onset of end-stage renal disease and their age-and sex-matched normotensive controls (Lewis, n ϭ 6). Animals were euthanized, and the aorta was collected to measure calcium content by atomic absorption spectrophotometry. A separate cohort of animals (n ϭ 5/group) were anesthetized with pentobarbitone sodium and pressure perfused with formalin, and the aorta was collected for histomorphometry, which allowed calculation of aortic wall thickness, medial crosssectional area (MCSA), elastic modulus (EM), and wall stress (WS), size and density of smooth muscle nuclei, and relative content of lamellae, interlamellae elastin, and collagen. Mean arterial pressure (MAP) and PWV were significantly greater in the LPK compared with Lewis (72 and 33%, respectively) animals. The LPK group had 6.8-fold greater aortic calcification, 38% greater aortic MCSA, 56% greater EM/WS, 13% greater aortic wall thickness, 21% smaller smooth muscle cell area, and 20% less elastin density with no difference in collagen fiber density. These findings demonstrate vascular remodeling and increased calcification with a functional increase in PWV and therefore aortic stiffness in hypertensive LPK rats.
AJP: Renal Physiology, 2012
Vavrinec P, Henning RH, Goris M, Vavrincova-Yaghi D, Buikema H, van Dokkum RP. Vascular smooth muscle function of renal glomerular and interlobar arteries predicts renal damage in rats. ). In this study, we investigated whether preexisting glomerular vascular integrity predicts subsequent renal damage after 5/6Nx, using in vivo intravital microscopy and in vitro myogenic constriction of small renal arteries. Moreover, we aimed to elucidate the role of renal ANG II type 1 receptor (AT1R) expression in this model. Anesthetized rats underwent intravital microscopy to visualize constriction to ANG II of glomerular afferent and efferent arterioles, with continuous measurement of blood pressure, heart rate, and renal blood flow. Thereafter, 5/6Nx was performed, interlobar arteries were isolated from the extirpated kidney, and myogenic constriction was assessed in a perfused vessel setup. Blood pressure and proteinuria were assessed weekly for 12 wk, and focal glomerulosclerosis (FGS) was determined at the end of study. Relative expression AT1R in the kidney cortex obtained at 5/6Nx was determined by PCR. Infusion of ANG II induced significant constriction of both afferent and efferent glomerular arterioles, which strongly positively correlated with proteinuria and FGS at 12 wk after 5/6Nx. Furthermore, in vitro measured myogenic constriction of small renal arteries negatively correlated with proteinuria 12 wk after 5/6Nx. Moreover, in vivo vascular reactivity negatively correlated with in vitro reactivity. Additionally, relative expression of AT1R positively correlated with responses of glomerular arterioles and with markers of renal damage. Both in vivo afferent and efferent responses to ANG II and in vitro myogenic constriction of small renal arteries in the healthy rat predict the severity of renal damage induced by 5/6Nx. This vascular responsiveness is highly dependent on AT1R expression. Intraorgan vascular integrity may provide a useful tool to guide the prevention and treatment of renal end-organ damage.
Pathophysiology of Vascular Remodeling in Hypertension
International Journal of Hypertension, 2013
Vascular remodeling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Glagov’s contribution. We then move to some basic concepts on the biomechanics of blood vessels and explain the definitions proposed by Mulvany for specific forms of remodeling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodeled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodeling is described, again with emphasis on human data. Some details are given on the three mechanisms to date which point to remodeling resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remo...
Vascular Remodeling in Experimental Hypertension
The Scientific World JOURNAL, 2005
The basic hemodynamic abnormality in hypertension is an increased peripheral resistance that is due mainly to a decreased vascular lumen derived from structural changes in the small arteries wall, named (as a whole) vascular remodeling. The vascular wall is an active, flexible, and integrated organ made up of cellular (endothelial cells, smooth muscle cells, adventitia cells, and fibroblasts) and noncellular (extracellular matrix) components, which in a dynamic way change shape or number, or reorganize in response to physiological and pathological stimuli, maintaining the integrity of the vessel wall in physiological conditions or participating in the vascular changes in cardiovascular diseases such as hypertension. Research focused on new signaling pathways and molecules that can participate in the mechanisms of vascular remodeling has provided evidence showing that vascular structure is not only affected by blood pressure, but also by mechanisms that are independent of the increas...
Vascular Dysfunction as Target Organ Damage in Animal Models of Hypertension
International Journal of Hypertension, 2012
Endothelial dysfunction is one of the main characteristics of chronic hypertension and it is characterized by impaired nitric oxide (NO) bioactivity determined by increased levels of reactive oxygen species. Endothelial function is usually evaluated by measuring the vasodilation induced by the local NO production stimulated by external mechanical or pharmacological agent. These vascular reactivity tests may be carried out in different models of experimental hypertension such as NO-deficient rats, spontaneously hypertensive rats, salt-sensitive rats, and many others. Wire myograph and pressurized myograph are the principal methods used for vascular studies. Usually, increasing concentrations of the vasodilator acetylcholine are added in cumulative manner to perform endothelium-dependent concentration-response curves. Analysis of vascular mechanics is relevant to identify arterial stiffness. Both endothelial dysfunction and vascular stiffness have been shown to be associated with incr...
Vascular growth responses in SHR and WKY during development of renal (1K1C) hypertension
1997
Intrinsic differences between vascular smooth mm 2 and 1.66 { 0.15 1 10 4 mm 2 , respectively. Likewise, the number of VSMCs ( within a precise muscle cells ( VSMC ) in normotension and genetic hypertension may account for the exaggerated anatomical site of the mesenteric vasculature ) were not different between the RH-SHR and the growth response often observed in the hypertensive vasculature. To test this hypothesis, RH 0.22 -WKY with VSMC number 7.6 { 0.8 1 10 4 cells and 6.9 { 0.4 1 10 4 cells, respectively. In the in this study we compared the vascular growth response of the spontaneously hypertensive rat RH 0.22 -WKY vascular growth responses were generally unchanged compared with the RH 0.24 -( SHR ) and Wistar-Kyoto rat ( WKY ) following induction of one kidney, one clip ( 1K1C ) renal WKY except for a further increase in the incidence of polyploid cells. In conclusion, the results of hypertension. SHR and WKY rats were uninephrectomized and renal hypertension (RH) this study demonstrate that smooth muscle cells of the SHR are not hyperresponsive to all growth-induced using silver clips of 0.22 and 0.24 mm width. Four weeks later, vessel and VSMC growth promoting stimuli. Taken together with previous observations, it appears that sustained activity of were assessed in small mesenteric arteries. The systolic blood pressure ( SBP ) in the RH animals the renin-angiotensin system may be required for exaggerated vascular growth responses in SHR. was significantly higher than in uninephrectomised controls, in RH-SHR with a ᭧ 1997 American Journal of Hypertension, Ltd. Am J Hypertens 1997; 10:43 -50 0.24 mm clip SBP averaged 215 { 4 mm Hg and in RH-WKY with a 0.22 or 0.24 mm clip the SBPs averaged 214 { 5 mm Hg and 190 { 2 mm Hg, respectively. For the same SBP, there were no KEY WORDS: One kidney-one clip hypertension, vascular growth, vascular smooth muscle, differences in medial cross-sectional areas of the small mesenteric arteries between RH-SHR and spontaneously hypertensive rat, Wistar-Kyoto rat, renal hypertension. RH 0.22 -WKY, which averaged 1.73 { 0.19 1 10 4
Heliyon, 2020
The vascular amplifier in hypertension is a result of structural changes in resistance arteries. We estimated the vascular amplifier hypertensive:normotensive (H:N) ratio in the renal bed compared with the total peripheral bed in conscious rabbits during infusion of vasoconstrictor and vasodilator stimuli. Methods: Rabbits were subjected to bilateral renal cellophane wrap or sham operation. A perivascular ultrasonic flow probe was implanted on the left renal artery to measure renal blood flow. A catheter was inserted into the thoracic aorta for agonist administration. Blood pressure, heart rate and renal blood flow were measured on three separate days in conscious rabbits with intact effectors, ganglionic block or neurohumoral block. Dose-response curves were constructed to intra-arterial infusion of noradrenaline, angiotensin II, adenosine and acetylcholine. Results: Resting renal vascular resistance in hypertensive rabbits was markedly decreased by ganglionic block and further by neurohumoral block. With effectors intact, ganglionic block or neurohumoral block, the H:N ratio for renal vascular resistance was 2.32, 1.72 or 1.72, respectively. The ratio was generally maintained during the infusion of constrictor and dilator drugs although distortions occurred at higher concentrations of constrictor or dilator drugs. Conclusions: Estimation of the renal resistance amplifier in renal wrap hypertension with neurohumoral block accords with our earlier estimates of the total peripheral resistance amplifier (1.79). This vascular resistance amplifier is consistent with a decrease in internal radius through structural remodelling in the renal vascular bed as is reflected in the total arterial circulation in hypertension.