Immunohistochemical evaluation of microvascular rarefaction in hypertensive humans and in spontaneously hypertensive rats

Paiardi, Silvia; Rodella, Luigi Fabrizio; Ciuceis, Carolina De; Porteri, Enzo; Boari, Gianluca E.M.; Rezzani, Rita; Rizzardi, Nicola; Platto, Caterina; Tiberio, Guido A M; Giulini, Stefano Maria; Rizzoni, Damiano; Agabiti‐Rosei, Enrico

doi:10.3233/ch-2009-1195

Cited by 54 publications

(30 citation statements)

References 38 publications

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“…[44,45,4] Our data suggest that ischemic hind-limb from mice treated with L-NAME or Ang II display a significant reduction in capillary density compared to sham. Sham and hypertensive mice treated with SN show a significant increase in capillary density, indicating that SN is a potent promoter of vascular growth.…”

Section: Discussionmentioning

confidence: 86%

Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension

Amin

Choi

Osman-Elazeik

et al. 2012

Pflugers Arch - Eur J Physiol

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Background Arterial hypertension is a major risk factor that can lead to complication of peripheral vascular disease due, in part, to endothelial dysfunction. Because sodium nitrite (SN) can be converted to nitric oxide (NO), which counteracts endothelial dysfunction, we explored the effect of nitrite on neovascularization following hind-limb ischemia in different models of hypertension (HT). Methods and results Chronic delivery of angiotensin-II (Ang-II, 400ng/Kg/min) or N(omega)-nitro-L-arginine-methyl-ester (L-NAME, 0.1g/L) were used for a two week period to induce hypertension. Mice were subjected to femoral artery ligation induced-ischemia in the hind-limb followed by treatment with SN (50mg/L) for 2-weeks. SN significantly reduced systolic arterial blood pressure in mice receiving Ang-II and L-NAME, but had no effect in sham animals. After 2 weeks, blood flow and microangiography showed 60%±1.0 recovery in sham compared to 40%±1.3 in HT mice. Importantly, sham and HT mice treated with SN showed a 100% blood flow recovery associated with normalization in capillary density. The inhibition of xanthine-oxido-reductase (allopurinol) or VEGFR (SU-5416) prevented the neovascularization in HT mice treated with SN. Cyclic GMP (cGMP) content in the hind-limb was significantly increased in mice treated with SN compared to non-treated mice. Nitrite/nitrate content was only increased in the sham group treated with SN. Immunoprecipitation and Western blot analysis revealed an increase in eNOS/Akt/VEGFR phosphorylation in skeletal muscle from mice treated with SN compared to non-treated mice. Conclusion Our findings indicate that SN therapy rescues the neovascularization and blood flow recovery in ischemic hind-limb of sham and HT mice likely through the Akt/NO/cGMP and VEGFR pathways.

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Section: Discussionmentioning

confidence: 86%

Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension

Amin

Choi

Osman-Elazeik

et al. 2012

Pflugers Arch - Eur J Physiol

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“…However, the lower beta-type platelet-derived growth factor receptor expression in the brain of hypertensive mice suggests possible negative effects on arterioles and capillaries. Here, hypertension-induced pericyte loss could contribute to vessel rarefaction (Suzuki et al 2003;Paiardi et al 2009) that ultimately affects regional cerebral blood flow with deleterious consequences for, e.g., white matter integrity (Jiwa et al 2010;Joutel et al 2010). Besides the observed structural alterations of cerebral arteries, an L-NAME-mediated inhibition of endothelial nitric oxide synthases activity may as well impair vascular function and hence, the regulation of vascular tone and adequate tissue perfusion (Luscher 1990;Schiffrin et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Structural and functional brain alterations in a murine model of Angiotensin II‐induced hypertension

Meißner

Minnerup

Sòria

et al. 2016

Journal of Neurochemistry

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Hypertension is a main risk factor for the development of cerebral small vessel disease (cSVD) - a major contributor to stroke and the most common cause of vascular dementia. Despite the increasing socioeconomic importance arising from cSVD, currently only a few specific treatment strategies with proven efficacy are known. Fundamental to the lack of specific treatments is poor understanding of the disease pathogenesis and a lack of appropriate animal models resembling all symptoms of the human disease. However, chronic hypertensive rat models have been shown to bear similarities to most key features of cSVD. Despite a significantly larger toolbox available for genotypic and phenotypic modifications compared to rats, mouse models of hypertension are unusual when modeling cSVD and associated cognitive impairment experimentally. In the present study, we therefore characterized hypertension-mediated cerebrovascular alterations and accompanying structural and functional consequences by simultaneously treating adult wild-type mice (C57BL/6N) with Angiotensin II (AngII) and the nitric oxide synthases inhibitor L-NAME for 4 weeks. Hypertension associated to cerebral alterations reminiscent of early-onset cSVD and vascular cognitive impairment when combined with additional AngII bolus injections. Most importantly, preventing the elevation of blood pressure (BP) protected from the development of cSVD symptoms and associated cognitive decline. Our data strongly support the suitability of this particular mouse model of AngII-induced hypertension as an appropriate animal model for early-onset cSVD and hence, vascular cognitive impairment, pathologies commonly preceding vascular dementia.

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“…In the SHR, systolic blood pressure begins to rise at 5 to 6 weeks of age and may reach 180 mmHg by 15 weeks old, while the pressure of a normotensive rat is around 130 mmHg [23,35]. By this age, microvascular rarefaction has been documented in numerous tissues including skeletal muscle, cardiac muscle, kidney, and the brain of SHR [22,28,32,36,38,39]. Microvascular rarefaction has also been documented in the SHR mesentery [4,16,32].…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis in Mesenteric Microvascular Networks from Spontaneously Hypertensive Versus Normotensive Rats

2011

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Elevated blood pressure during hypertension has been associated with microvascular rarefaction defined by loss of microvessels. However, whether rarefaction is a result of impaired angiogenesis remains unclear. The objective of this study was to compare angiogenesis across the time course of mesenteric microvascular network remodeling in adult spontaneously hypertensive versus normotensive rats. Angiogenic responses in 15–16-week-old SHR and Wistar rats at 0, 3, 5, 10 or 25 days post 20 minute exteriorization of the mesentery were quantified. Consistent with the phenomenon of rarefaction, vascularized area in unstimulated SHR was decreased compared to Wistar. By 25 days, SHR vascular area had increased to the Wistar level and vascular length density and capillary sprouting were comparable. At 3 and 5 days, SHR and Wistar tissues displayed an increase in the capillary sprouting and vascular density relative to their unstimulated controls. At 10 days, capillary sprouting in the SHR remained elevated. The percent change in vascular density was elevated in the SHR compared to the Wistar group at 3 and 5 days and by 25 days the rate of change was more negative. Our results suggest that SHR networks undergo an increased rate of growth followed by an increased rate of pruning.

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Immunohistochemical evaluation of microvascular rarefaction in hypertensive humans and in spontaneously hypertensive rats

Cited by 54 publications

References 38 publications

Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension

Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension

Structural and functional brain alterations in a murine model of Angiotensin II‐induced hypertension

Angiogenesis in Mesenteric Microvascular Networks from Spontaneously Hypertensive Versus Normotensive Rats

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