A Novel Aortic Coarctation Model for Studying Hypertension in the Pig

Fossum, Theresa W.; Baltzer, Wendy I.; Miller, Matthew W.; Aguirre, M.E. Erro; Whitlock, Debbi; Solter, Phil F.; Makarski, Lori A.; McDonald, Michelle M.; An, Mi Young; Humphrey, Jay D.

doi:10.1080/08941930390153032

Cited by 14 publications

(9 citation statements)

References 12 publications

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“…Animal care in this study was approved by the University Animal Care Committee, Texas A&M University. Our porcine aortic coarctation model of hypertension was described previously (10). Briefly, inflatable silicone occluders (8 -12 mm, In Vivo Metrics; reinforced by Solomon Scientific) were surgically implanted around the aorta proximal to the diaphragm of Yucatan micro-miniswine (8 -11 mo).…”

Section: Methodsmentioning

confidence: 99%

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Transforming growth factor-β signaling in hypertensive remodeling of porcine aorta

Popović

Bridenbaugh

Neiger

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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A porcine aortic coarctation model was used to examine regulation of gene expression in early hypertensive vascular remodeling. Aortic segments were collected proximal (high pressure) and distal (low pressure) to the coarctation after 2 wk of sustained hypertension (mean arterial pressure > 150 mmHg). Porcine 10K oligoarrays used for gene expression profiling of the two regions of aorta revealed downregulation of cytoskeletal and upregulation of extracellular region genes relative to the whole genome. A genomic database search for transforming growth factor-β (TGF-β) control elements showed that 19% of the genes that changed expression due to hypertension contained putative TGF-β control elements. Real-time RT-PCR and microarray analysis showed no change in expression of TGF-β1, TGF-β2, TGF-β3, or bone morphogenetic proteins-2 and -4, yet immunohistochemical staining for phosphorylated SMAD2, an indicator of TGF-β signaling, and for phosphorylated SMAD1/5/8, an indicator of signaling through the bone morphogenetic proteins, showed the highest percentage of positively stained cells in the proximal aortic segments of occluded animals. For TGF-β signaling, this increase was significantly different than for sham-operated controls. Western blot analysis showed no difference in total TGF-β1 protein levels with respect to treatment or aortic segment. Immunohistochemistry showed that the protein levels of latency-associated peptide was decreased in proximal segments of occluded animals. Collectively, these results suggest that activation of TGF-β, but not altered expression, may be a major mechanism regulating early hypertensive vascular remodeling.

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Section: Methodsmentioning

confidence: 99%

“…Using the porcine aortic coarctation model presented (10), our laboratory recently showed that increased pro-collagen I synthesis, a known consequence of TGF-␤ activity, and increased smooth muscle proliferation occurred early in hypertension. In contrast, changes in contractile protein expression continued over an 8-wk period (13).…”

mentioning

confidence: 99%

Transforming growth factor-β signaling in hypertensive remodeling of porcine aorta

Popović

Bridenbaugh

Neiger

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Our aortic coarctation model for studying hypertension in the mini-pig is described elsewhere (Fossum et al 2003). Briefly, a balloon-expandable occluder is prefilled with a 50% dextrose solution, placed over a Gore-Tex soft tissue patch sheet, and secured with sutures around the aorta proximal to the diaphragm.…”

Section: Animal Modelmentioning

confidence: 99%

Time Courses of Growth and Remodeling of Porcine Aortic Media During Hypertension: A Quantitative Immunohistochemical Examination

Ambrus

Fossum

et al. 2007

J Histochem Cytochem.

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(EW) S U M M A R Y Arteries undergo marked structural and functional changes in human and experimental hypertension that generally involve smooth muscle cell (SMC) hypertrophy/ hyperplasia as well as abnormal extracellular matrix turnover. In this study we examined time courses of changes in SMC activity and matrix protein content in a novel mini-pig aortic coarctation model. Cell proliferation was evaluated by immunostaining of Ki-67, apoptosis was assessed by TUNEL, and phenotypic changes were monitored by immunostaining three SMC contractile markers (caldesmon, calponin, and smoothelin). Changes in medial collagen and elastin were examined by picrosirius red and Verhoeff-van Gieson staining, respectively. LabVIEW-based image analysis routines were developed to objectively and efficiently quantify the (immuno)histochemical results. We found that significant cell proliferation and matrix production occurred in the early stages of this coarctation model and then declined gradually; the SMCs also tended to exhibit a less contractile phenotype following these cellular and extracellular changes. Specifically, different aspects of the phenotypic changes associated with hypertension occurred at different rates: cell proliferation and collagen production occurred early and peaked by 2 weeks, whereas changes in contractile protein expression continued to decrease over the entire 8-week study period. Temporal changes found in this study emphasize the importance of simultaneously tracing time courses of SMC growth and differentiation as well as matrix protein production and content. SMCs are multifunctional, and caution must be used to not overdefine phenotype. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 56:359-370, 2008)

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“…Renovascular hypertension was produced in pigs via suprarenal aortic coarctation as described in our previous study. 16 Briefly, hypertension was induced in 6 mature (8-to 11-month-old) male, micro-minipigs (Sinclair Research Center, Inc, Columbia, Mo) weighing between 21 and 37 kg. Systemic blood pressure of the animals was monitored by telemetry.…”

Section: Animal Modelmentioning

confidence: 99%

Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide–Mediated Dilation of Coronary Arterioles

et al. 2004

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Abstract-One characteristic of hypertension is a decreased endothelium-dependent nitric oxide (NO)-mediated vasodilation; however, the underlying mechanism is complex. In endothelial cells (ECs), L-arginine is the substrate for both NO synthase (NOS) and arginase. Because arginase has recently been shown to modulate NO-mediated dilation of coronary arterioles by reducing L-arginine availability, we hypothesized that upregulation of vascular arginase in hypertension contributes to decreased NO-mediated vasodilation. To test this hypothesis, hypertension (mean arterial blood pressure Ͼ150 mm Hg) was maintained for 8 weeks in pigs by aortic coarctation. Coronary arterioles from normotensive (NT) and hypertensive (HT) pigs were isolated and pressurized for in vitro study. NT vessels dilated dose-dependently to adenosine (partially mediated by endothelial release of NO) and sodium nitroprusside (endothelium-independent vasodilator). Conversely, HT vessels exhibited reduced dilation to adenosine but dilated normally to sodium nitroprusside. Adenosine-stimulated NO release was increased Ϸ3-fold in NT vessels but was reduced in HT vessels. Moreover, arginase activity was 2-fold higher in HT vessels. Inhibition of arginase activity by N -hydroxynor-L-arginine or incubation with L-arginine partially restored NO release and dilation to adenosine in HT vessels. Immunohistochemistry showed that arginase expression was increased but NOS expression was decreased in arteriolar ECs of HT vessels. These results suggest that NO-mediated dilation of coronary arterioles is inhibited in hypertension by an increase in arginase activity in EC, which limits L-arginine availability to NOS for NO production. The inability of arginase blockade or L-arginine supplementation to completely restore vasodilation may be related to downregulation of endothelial NOS expression. Key Words: arginine Ⅲ hypertension Ⅲ microcirculation Ⅲ nitric oxide synthase Ⅲ vasodilation H ypertension is a major risk factor for coronary artery disease. One characteristic of hypertension that appears to be critical in the development of vascular disease is the impairment of endothelial function. For example, there is a markedly reduced endothelium-dependent vasodilation in both large and small coronary arteries from hypertensive humans and animal models of hypertension. 1 Mounting evidence suggests that this vascular impairment may be related to a diminished production and bioavailability of the potent vasodilator nitric oxide (NO), which may result from an increased vascular production of superoxide anion 2 or decreased endothelial levels of tetrahydrobiopterin 3,4 or L-arginine. 5 Interestingly, administration of NO precursor L-arginine restores endothelium-mediated vasodilatory function in patients with essential hypertension, 5 improves coronary hemodynamics in spontaneously hypertensive rats, 6 and increases NO production and reduces blood pressure in hypertensive rats with 7 or without 8 renal failure. These results suggest the possible reduction of L-arginine ...

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A Novel Aortic Coarctation Model for Studying Hypertension in the Pig

Cited by 14 publications

References 12 publications

Transforming growth factor-β signaling in hypertensive remodeling of porcine aorta

Transforming growth factor-β signaling in hypertensive remodeling of porcine aorta

Time Courses of Growth and Remodeling of Porcine Aortic Media During Hypertension: A Quantitative Immunohistochemical Examination

Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide–Mediated Dilation of Coronary Arterioles

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