Age and sex dependency of thoracic aortopathy in a mouse model of Marfan syndrome.

Thoracic aortic aneurysm is one of the manifestations of Marfan syndrome (MFS) that is known to affect men more severely than women. However, the incidence of MFS is similar between men and women. The aim of this study is to show that during pathological aortic dilation, sex-dependent severity of thoracic aortopathy in a mouse model of MFS translates into sex-dependent alterations in cells and matrix of the ascending aorta, consequently affecting aortic biomechanics. Fibrillin-1 C1041G/+ (Het) mice were used as a mouse model of MFS. Ultrasound measurements from 3 to 12 mo showed increased aortic diameter in Het aorta, with larger percentage increase in diameter for males compared with females. Immunohistochemistry showed decreased contractile smooth muscle cells in Het aortic wall compared with healthy aorta, which was accompanied by decreased contractility measured by wire myography. Elastin autofluorescence, second-harmonic generation microscopy of collagen fibers, and passive biomechanical assessments using myography showed more severe damage to elastin fibers, increased medial fibrosis, and increased stiffness of the aortic wall in MFS males but not females. Male and female Het mice showed increased expression of Sca-1-positive adventitial progenitor cells versus controls at young ages. In agreement with clinical data, Het mice demonstrate sex-dependent severity of thoracic aortopathy. It was also shown that aging exacerbates the disease state especially for males. Our findings suggest that female mice are protected from progression of aortic dilation at early ages, leading to a lag in aneurysm growth.NEW & NOTEWORTHY Male Fbn1C1041G/+ mice show more severe thoracic aortic changes compared with females, especially at 12 mo of age. Up to 6 mo of age, Sca-1+ smooth muscle progenitor cells are more abundant in the adventitia of both male and female Fbn1 Het mice compared with wild types (WTs). Male and female Het mice show similar patterns of expression of Sca-1+ cells at early ages.

Developmental origins of mechanical homeostasis in the aorta.

BACKGROUND: Mechanical homeostasis promotes proper aortic structure and function. Pathological conditions may arise, in part, from compromised or lost homeostasis. There is thus a need to quantify the homeostatic state and when it emerges. Here we quantify changes in mechanical loading, geometry, structure, and function of the murine aorta from the late prenatal period into maturity. RESULTS: Our data suggest that a homeostatic set-point is established by postnatal day P2 for the flow-induced shear stress experienced by endothelial cells; this value deviates from its set-point from P10 to P21 due to asynchronous changes in mechanical loading (flow, pressure) and geometry (radius, wall thickness), but is restored thereafter consistent with homeostasis. Smooth muscle contractility also decreases during this period of heightened matrix deposition but is also restored in maturity. The pressure-induced mechanical stress experienced by intramural cells initially remains low despite increasing blood pressure, and then increases while extracellular matrix accumulates. CONCLUSIONS: These findings suggest that cell-level mechanical homeostasis emerges soon after birth to allow mechanosensitive cells to guide aortic development, with deposition of matrix after P2 increasingly stress shielding intramural cells. The associated tissue-level set-points that emerge for intramural stress can be used to assess and model the aorta that matures biomechanically by P56.

Aortic Arch Enlargement and Coarctation Repair of Preserving the Lesser Curvature of the Aortic Arch Through a Left Thoracotomy in Neonates.

The aim of this study was to analyze the aortic arch repair technique for preserving the lesser curvature without cardiopulmonary bypass through a left thoracotomy in neonates with coarctation of the aorta (CoA) and a hypoplastic distal aortic arch (HDAA). HDAA was defined as z-score of the aortic arch < - 2.5. Twenty-four neonates with CoA and HDAA were retrospectively studied. Patients underwent enlargement of the HDAA associated with CoA repair when their z-scores were < - 4. They were divided into 2 groups on the basis of the preoperative z-score of the distal aortic arch: group 1 (n = 14), z-score ≥ - 4; group 2 (n = 10), z-score < - 4. Twenty-two patients had intracardiac defects. Follow-up ranged from 0.9 to 20.1 years (median 11.6 years). The z-scores of the distal aortic arch were significantly smaller in group 2 than group 1 (- 5.09 ± 1.05 vs - 3.19 ± 0.36, p < 0.001). There were no hospital deaths and no hypertension. All dimensions of the aortic arch in both groups revealed significant catch-up growth (p < 0.02). All patients showed a pressure gradient ≤ 5 mmHg across the aortic arch and between the arms and legs at the latest follow-up. Two patients showed an angulated arch deformity over 10 years later. This technique provided good catch-up growth and a low incidence of reobstruction and deformity of reconstructed aortic arch in both groups. These results suggest that this modification might be considered as one choice of technique for CoA and HDAA.

Outcomes of Early-Onset Acute Type A Aortic Dissection　- Influence of Etiologic Factors.

BACKGROUND: Outcomes of early-onset acute type A aortic dissection (ATAAD) associated with Marfan syndrome (MFS) are known, but not with other etiologies. Methods and Results: ATAAD patients from 2 centers (n=1,001) were divided into 2 groups: age ≤45 years (n=93) and age >45 years (n=908). Although in-hospital death and 10-year survival were similar (12% vs. 7% and 62.6% vs. 67.3%), the 10-year aortic event-free survival differed (50.0% vs. 80.2%; P<0.01). ATAAD patients from 3 centers (n=132), all aged ≤45 years, were divided into 5 groups: lone hypertension (HTN, n=71), MFS (n=23), non-syndromic familial thoracic aortic aneurysm and dissection (NS-FTAAD, n=16), bicuspid aortic valve (BAV, n=11), and no known etiologic factor (n=11). The incidence of severe aortic insufficiency varied between groups (HTN: 11%, MFS: 39%, NS-FTAAD: 38%, BAV: 55%, no known factor: 46%; P<0.01), whereas in-hospital death did not (14%, 22%, 0%, 0%, and 9%; P=0.061). The 10-year survival was 52.2%, 64.7%, 83.6%, 100%, and 90.9%, respectively, and 10-year aortic event-free survival was 55.6%, 36.3%, 77.5%, 90.0%, and 30.0%. Median descending aorta growth (mm/year) was 1.1 (0.1-3.4), 2.3 (0.3-5.3), 1.9 (1.3-2.7), 0.9 (-0.1-2.0), and 1.0 (-0.2-2.9) (P=0.15), respectively. CONCLUSIONS: Late aortic events are common in young ATAAD patients. Known etiologic factors, though not BAV, negatively influence late outcomes in these patients.

Manganese porphyrin redox state in endothelial cells: Resonance Raman studies and implications for antioxidant protection towards peroxynitrite.

Cationic manganese(III) ortho N-substituted pyridylporphyrins (MnP) act as efficient antioxidants catalyzing superoxide dismutation and accelerating peroxynitrite reduction. Importantly, MnP can reach mitochondria offering protection against reactive species in different animal models of disease. Although an LC-MS/MS-based method for MnP quantitation and subcellular distribution has been reported, a direct method capable of evaluating both the uptake and the redox state of MnP in living cells has not yet been developed. In the present work we applied resonance Raman (RR) spectroscopy to analyze the intracellular accumulation of two potent MnP-based lipophilic SOD mimics, MnTnBuOE-2-PyP5+ and MnTnHex-2-PyP5+ within endothelial cells. RR experiments with isolated mitochondria revealed that the reduction of Mn(III)P was affected by inhibitors of the electron transport chain, supporting the action of MnP as efficient redox active compounds in mitochondria. Indeed, RR spectra confirmed that MnP added in the Mn(III) state can be incorporated into the cells, readily reduced by intracellular components to the Mn(II) state and oxidized by peroxynitrite. To assess the combined impact of reactivity and bioavailability, we studied the kinetics of Mn(III)TnBuOE-2-PyP5+ with peroxynitrite and evaluated the cytoprotective capacity of MnP by exposing the endothelial cells to nitro-oxidative stress induced by peroxynitrite. We observed a preservation of normal mitochondrial function, attenuation of cell damage and prevention of apoptotic cell death. These data introduce a novel application of RR spectroscopy for the direct detection of MnP and their redox states inside living cells, and helps to rationalize their antioxidant capacity in biological systems.

Clinical outcomes and rates of aortic growth and reoperation after 1-stage repair of extensive chronic thoracic aortic dissection.

OBJECTIVE: The study objective was to analyze clinical outcomes, distal segmental aortic growth, and aortic reoperation rates after 1-stage open repair of extensive chronic thoracic aortic dissection via bilateral anterior thoracotomy. METHODS: Eighty patients underwent extensive 1-stage repair of chronic aortic dissection that included the ascending aorta, the entire aortic arch, and the varying lengths of the descending thoracic aorta. One half or more of the descending thoracic aorta was replaced in 62 (78%) of the 80 patients. Hospital mortality was 2.5% (2 patients). Stroke occurred in 1 patient (1.2%), spinal cord ischemic injury occurred in 1 patient (1.2%), and renal failure requiring long-term dialysis occurred in 2 patients (2.5%). Sixty-five of the 78 hospital survivors (83%) had serial imaging studies suitable for calculation of growth rates of the remaining dissected thoracic and abdominal aorta. Forty-seven patients were followed for more than 5 years, and 21 patients were followed for more than 10 years. RESULTS: The mean annual growth rate for the distal contiguous aorta was 1.7 mm/y. Forty aortas increased in diameter, 16 aortas remained unchanged, and 9 aortas decreased in diameter. Five patients required reoperation on the contiguous thoracic or abdominal aorta 8, 27, 34, 51, and 174 months postoperatively for progressive enlargement. Actuarial freedom from reoperation on the contiguous aorta at 5 and 10 years was 95.4% and 93%, respectively. Actuarial freedom from any aortic reoperation at 5 and 10 years was 89.2% and 84.4%, respectively. Actuarial survival for the entire cohort at 5 and 10 years was 76.4% and 52.6%, respectively, and survival free of any aortic operation was 68.6% and 43.9%, respectively. No patient whose cause of death was known died of aortic rupture. CONCLUSIONS: Our extended experience with the 1-stage open procedure confirms its safety and durability for treatment of chronic aortic dissection with enlargement confined to the thoracic aorta. The procedure is associated with low operative risk and a low incidence of reoperation on the contiguous aorta. It represents a suitable alternative to the 2-stage, frozen elephant trunk, and hybrid procedures that are also used to treat this condition.

Prognostic significance of early aortic remodeling in acute uncomplicated type B aortic dissection and intramural hematoma.

BACKGROUND: Patients with Stanford type B aortic dissections (ADs) are at risk of long-term disease progression and late complications. The aim of this study was to evaluate the natural course and evolution of acute type B AD and intramural hematomas (IMHs) in patients who presented without complications during their initial hospital admission and who were treated with optimal medical management (MM). METHODS: Databases from 2 aortic centers in Europe and the United States were used to identify 136 patients with acute type B AD (n = 92) and acute type B IMH (n = 44) who presented without complications during their index admission and were treated with MM. Computed tomography angiography scans were available at onset (≤14 days) and during follow-up for those patients. Relevant data, including evidence of adverse events during follow-up (AE; defined according to current guidelines), were retrieved from medical records and by reviewing computed tomography scan images. Aortic diameters were measured with dedicated 3-dimensional software. RESULTS: The 1-, 2-, and 5-year event-free survival rates of patients with type B AD were 84.3% (95% confidence interval [CI], 74.4-90.6), 75.4% (95% CI, 64.0-83.7), and 62.6% (95% CI, 68.9-73.6), respectively. Corresponding estimates for IMH were 76.5% (95% CI, 57.8-87.8), 76.5% (95% CI, 57.8-87.8), and 68.9% (95% CI, 45.2-83.9), respectively. In patients with type B AD, risk of an AE increased with aortic growth within the first 6 months after onset. A diameter increase of 5 mm in the first half year was associated with a relative risk for AE of 2.29 (95% CI, 1.70-3.09) compared with the median 6 months' growth of 2.4 mm. In approximately 60% of patients with IMH, the abnormality resolved within 12 months and in the patients with nonresolving IMH, risk of an adverse event was greatest in the first year after onset and remained stable thereafter. CONCLUSIONS: More than one third of patients with initially uncomplicated type B AD suffer an AE under MM within 5 years of initial diagnosis. In patients with nonresolving IMH, most adverse events are observed in the first year after onset. In patients with type B AD an early aortic growth is associated with a greater risk of AE.

Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency.

OBJECTIVE: Williams syndrome is characterized by obstructive aortopathy attributable to heterozygous loss of ELN, the gene encoding elastin. Lesions are thought to result primarily from excessive smooth muscle cell (SMC) proliferation and consequent medial expansion, although an initially smaller caliber and increased stiffness of the aorta may contribute to luminal narrowing. The relative contributions of such abnormalities to the obstructive phenotype had not been defined. APPROACH AND RESULTS: We quantified determinants of luminal stenosis in thoracic aortas of Eln-/- mice incompletely rescued by human ELN. Moderate obstruction was largely because of deficient circumferential growth, most prominently of ascending segments, despite increased axial growth. Medial thickening was evident in these smaller diameter elastin-deficient aortas, with medial area similar to that of larger diameter control aortas. There was no difference in cross-sectional SMC number between mutant and wild-type genotypes at multiple stages of postnatal development. Decreased elastin content was associated with medial fibrosis and reduced aortic distensibility because of increased structural stiffness but preserved material stiffness. Elastin-deficient SMCs exhibited greater contractile-to-proliferative phenotypic modulation in vitro than in vivo. We confirmed increased medial collagen without evidence of increased medial area or SMC number in a small ascending aorta with thickened media of a Williams syndrome subject. CONCLUSIONS: Deficient circumferential growth is the predominant mechanism for moderate obstructive aortic disease resulting from partial elastin deficiency. Our findings suggest that diverse aortic manifestations in Williams syndrome result from graded elastin content, and SMC hyperplasia causing medial expansion requires additional elastin loss superimposed on ELN haploinsufficiency.

Geometry and growth of the reconstructed aorta in patients with hypoplastic left heart syndrome and variants.

OBJECTIVE: The interdigitating technique in aortic arch reconstruction in hypoplastic left heart syndrome and variants (HLHS) reduces the recoarctation rate. Little is known on aortic arch growth characteristics and resulting clinical impact. METHODS: A total of 139 patients with HLHS underwent staged palliation between 2007 and 2014; 73 patients underwent arch reconstruction. Dimensions of ascending aorta, transverse arch, interdigitating anastomosis, and descending aorta in pre-stage II and pre-Fontan angiograms were measured. Aortic arch dimensions were analyzed. Ventricular and atrioventricular valve function were assessed. RESULTS: Diameters increased in all segments between pre-stage II and pre-Fontan (P < .0005). The z scores remained unchanged in all segments but the descending aorta that was significantly larger pre-Fontan (P = .039). Dimensions and z scores between pre-stage II and pre-Fontan correlated in proximal segments, but not at and distal to the interdigitating anastomosis. Pronounced tapering occurred between the transverse arch and the interdigitating anastomosis. Arch intervention of any type was performed in 7 (9.6%), and intervention for recoarctation in 3 (4.1%) patients. CONCLUSIONS: The aortic arch after reconstruction with the interdigitating technique differs from normal. Growth was proportional with no further geometrical distortion. Recoarctation and reintervention rate is low. Further improvement may be achieved by optimizing patch configuration and material.

Morphometric changes in the aortic arch with advancing age in fetal to mature thoroughbred horses.

Aortic rupture is a well recognized cause of sudden death in thoroughbred horses. Some microscopic lesions, such as those caused by cystic medial necrosis and medionecrosis, can lead to aortic rupture. However, these microscopic lesions are also observed in normal horses. On the other hand, a previous study of aortic rupture suggested that underlying elastin and collagen deposition disorders might be associated with aortic rupture. Therefore, the purpose of this study was to compare the structural components of the tunica media of the aortic arch, which is composed of elastin, collagen, smooth muscle cells and mucopolysaccharides (MPS), in fetal to mature thoroughbred horses. The percentage area of elastin was greatest in the young horses and subsequently decreased with aging. The percentage area of collagen increased with aging, and the elderly horses (aged ≥20) exhibited significantly higher percentage areas of collagen than the young horses. The percentage area of smooth muscle cells did not change with age. The percentage area of MPS was inversely proportional to the percentage area of elastin. The fetuses exhibited a markedly larger percentage area of MPS than the mature horses. We concluded that the medial changes seen in the aortic arch, which included a reduction in the amount of elastin and increases in the amounts of collagen and MPS, were age-related variations.

Predictors of aortic growth in uncomplicated type B aortic dissection from the Acute Dissection Stent Grafting or Best Medical Treatment (ADSORB) database.

BACKGROUND: The high-risk patient cohort of uncomplicated type B aortic dissections (uTBADs) needs to be clarified. We compared uTBAD patients treated with best medical treatment (BMT), with and without aortic growth, from the Acute Dissection Stent Grafting or Best Medical Treatment (ADSORB) trial database. Furthermore, we looked for trends in outcome for aortic growth and remodeling after BMT and thoracic endovascular aortic repair (TEVAR) and BMT (TEVAR+BMT). METHODS: BMT patients with available baseline and a 1-year follow-up arterial computed tomography scan were identified. True lumen and false lumen diameter was assessed at baseline and at follow-up. Patients with false lumen growth (group I) and without false lumen growth (group II) were compared. Predictors of false lumen and total lumen (aortic) growth were identified. Lastly, BMT outcomes were compared with BMT+TEVAR for false lumen thrombosis and change in false lumen and total aortic diameter in four sections: 0 to 10 cm (A), 10 to 20 cm (B), 20 to 30 cm (C), and 30 to 40 cm (D) from the left subclavian artery. RESULTS: The dissection was significantly longer in group I than in group II (43.2 ± 4.9 cm vs 30.4 ± 8.8 cm; P = .002). The number of vessels originating from the false lumen at baseline was identified as an independent predictor of false lumen growth (odds ratio, 22.1; 95% confidence interval, 1.01-481.5; P = .049). Increasing age was a negative predictor of total aortic diameter growth (odds ratio, 0.902; 95% confidence interval, 0.813-1.00; P = .0502). The proximal sections A and B showed complete thrombosis in 80.6% in the BMT+TEVAR group compared with 9.5% in the BMT group. In these sections, changes from patent to partial or partial to complete thrombosis were observed in 90.3% of the TEVAR+BMT group vs 31.0% in the BMT group. In sections C and D, the change in thrombosis was 74.1% for the TEVAR+BMT group vs 20.6% for the BMT group. The false lumen diameter increase at section C was larger in the BMT group. Total lumen diameter decreased in sections A and B in the TEVAR+BMT group compared with an increase in the BMT group (-4.8 mm vs +2.9 mm, and -1.5 mm vs +3.8 mm, respectively). Sections C and D showed minimal and comparable expansion in both treatment groups. CONCLUSIONS: The new imaging analysis of the ADSORB trial patients identified the number of vessels originating from the false lumen as an independent predictor of false lumen growth in uTBAD patients. Increasing age was a negative predictor of aortic growth. Our analysis may help to identify which uTBAD patients are at higher risk and should receive TEVAR or be monitored closely during follow-up.

Aortic stenting in the growing sheep causes aortic endothelial dysfunction but not hypertension: Clinical implications for coarctation repair.

BACKGROUND: Stent implantation is the treatment of choice for adolescents and adults with aortic coarctation (CoAo). Despite excellent short-term results, 20%-40% of the patients develop arterial hypertension later in life, which was attributed to inappropriate response of the aortic baroreceptors to increased stiffness of the ascending aorta (ASAO), either congenital or induced by CoAo repair. In particular, it has been hypothesized that stent itself may cause or sustain hypertension. Therefore, we aimed to study the hemodynamic and structural impact following stent implantation in the normal aorta of a growing animal. METHODS: Eight female sheep completed the study and a stent was implanted in four. Every 3 mo we measured blood pressure of the anterior and posterior limbs and left ventricular function by echocardiography. Twelve months later invasive pressure was measured under baseline and simulated stress conditions. Expression of genes indicating oxidative stress (OS), endothelial dysfunction (ED) and stiffness, as well as pathological examination were performed in ascending (ASAO) and descending aorta (DSAO). RESULTS: SOD1 and MMP9 gene expression were higher in ASAO of the stented animals, compared to DSAO and controls, while NOS3 was decreased. No differences were found in blood pressure and echocardiographic parameters. No histological differences were found in the aorta of the two groups of animals. CONCLUSIONS: Stent does not affect central and peripheral hemodynamics, cardiac structure and function even in the long term. However, the finding of markers of OS and increased stiffness of ASAO, proximal to the stent, points to molecular mechanisms for increased cardiovascular risk of patients with stented CoAo.

A composite semiresorbable armoured scaffold stabilizes pulmonary autograft after the Ross operation: Mr Ross's dream fulfilled.

OBJECTIVES: Use of resorbable external reinforcement of the pulmonary autograft during the Ross operation has been suggested, but the differential regional potential for dilation of the aorta, mainly regarding the neo-root and the neo-Valsalva sinuses, represents an unresolved issue. Auxetic materials could be useful in preventing dilation given their favorable mechanical properties. We designed a composite semiresorbable armoured bioprosthesis constituted by polydioxanone and expanded polytetrafluoroethylene and evaluated its effectiveness as a pulmonary autograft reinforcement device in an animal model of the Ross procedure. METHODS: An experimental model of the Ross procedure was performed in 20 three-month-old growing lambs. The pulmonary autograft was alternatively nonreinforced (control group n = 10) or reinforced with composite bioprosthesis (reinforced group n = 10). Animals were followed up during growth for 6 months by angiography and echocardiography. Specific stainings for extracellular matrix and immunohistochemistry for metalloproteinase-9 were performed. RESULTS: Reference aortic diameter increased from 14 ± 1 mm to 19 ± 2 mm over 6 months of growth. In the control group, pulmonary autograft distension (28 ± 2 mm) was immediately noted, followed by aneurysm development at 6 months (40 ± 2 mm, P < .001 vs reference). In the reinforced group, an initial dilation to 18 ± 1 mm was detected and the final diameter was 27 ± 2 mm (42% increase). Two deaths due to pulmonary autograft rupture occurred in the control group. On histology, the control group showed medial disruption with connective fibrous replacement, whereas in the reinforced group compensatory intimal hyperplasia was present in the absence of intimal tears. The bioprosthesis promoted a positive matrix rearrangement process favoring neoarterialization and elastic remodeling as demonstrated on specific staining for elastin collagen and metalloproteinase-9. CONCLUSIONS: The device adapted and functionally compensated for the characteristics of autograft growth, guaranteeing a reasonable size of the autograft at 6 months, but more important, because the device is biocompatible, it did not disrupt the biological process of growth or cause inflammatory damage to the wall.

Segmental and age differences in the elastin network, collagen, and smooth muscle phenotype in the tunica media of the porcine aorta.

The porcine aorta is often used in studies on morphology, pathology, transplantation surgery, vascular and endovascular surgery, and biomechanics of the large arteries. Using quantitative histology and stereology, we estimated the area fraction of elastin, collagen, alpha-smooth muscle actin, vimentin, and desmin within the tunica media in 123 tissue samples collected from five segments (thoracic ascending aorta; aortic arch; thoracic descending aorta; suprarenal abdominal aorta; and infrarenal abdominal aorta) of porcine aortae from growing domestic pigs (n=25), ranging in age from 0 to 230 days. The descending thoracic aorta had the greatest elastin fraction, which decreased proximally toward the aortic arch as well as distally toward the abdominal aorta. Abdominal aortic segments had the highest fraction of actin, desmin, and vimentin positivity and all of these vascular smooth muscle markers were lower in the thoracic aortic segments. No quantitative differences were found when comparing the suprarenal abdominal segments with the infrarenal abdominal segments. The area fraction of actin within the media was comparable in all age groups and it was proportional to the postnatal growth. Thicker aortic segments had more elastin and collagen with fewer contractile cells. The collagen fraction decreased from ascending aorta and aortic arch toward the descending aorta. By revealing the variability of the quantitative composition of the porcine aorta, the results are suitable for planning experiments with the porcine aorta as a model, i.e. power test analyses and estimating the number of samples necessary to achieving a desirable level of precision. The complete primary morphometric data, in the form of continuous variables, are made publicly available for biomechanical modeling of site-dependent distensibility and compliance of the porcine aorta.

Study of the development of the mouse thoracic aorta three-dimensional macromolecular structure using two-photon microscopy.

Using the intrinsic optical properties of collagen and elastin, two-photon microscopy was applied to evaluate the three-dimensional (3D) macromolecular structural development of the mouse thoracic aorta from birth to 60 days old. Baseline development was established in the Scavenger Receptor Class B Type I-Deficient, Hypomorphic Apolipoprotein ER61 (SR-BI KO/ApoeR61(h/h)) mouse in preparation for modeling atherosclerosis. Precise dissection enabled direct observation of the artery wall in situ. En-face, optical sectioning of the aorta provided a novel assessment of the macromolecular structural development. During aortic development, the undulating lamellar elastin layers compressed consistent with the increases in mean aortic pressure with age. In parallel, a net increase in overall wall thickness (p<0.05, in day 60 compared with day 1 mice) occurred with age whereas the ratio of the tunicas adventitia and media to full aortic thickness remained nearly constant across age groups (~1:2.6, respectively). Histochemical analyses by brightfield microscopy and ultrastructure validated structural proteins and lipid deposition findings derived from two-photon microscopy. Development was associated with decreased decorin but not biglycan proteoglycan expression. This non-destructive 3D in situ approach revealed the aortic wall microstructure development. Coupling this approach with the intrinsic optical properties of the macromolecules may provide unique vascular wall 3D structure in many pathological conditions, including aortic atherosclerosis, dissections and aneurysms.

Structure and adaptation of arteries to pulsatile flow: the case of the ascending aorta.

PURPOSE: The objectives are: (i) assess the development of the impedance of some arteries during the first decades of life; (ii) determine the influence of pulse rate in arterial impedance; (iii) compare the structure of some arterial segments with optimized structures with respect to blood flow; and (iv) explain the elongation of the ascending aorta throughout life in healthy subjects. METHODS: A model of the arterial network previously developed by the authors, together with data of lengths, diameters, and distensibilities of arterial segments reported in the literature were used. The impedances of the aorta and carotid artery were calculated based on that model. Similarly, the impedances of various arteries corresponding to heart rates of 65 bpm and 120 bpm were calculated. Values observed in arterial segments were compared with the respective optimal values from the viewpoint of hemodynamic performance. This allowed drawing conclusions on the arterial segments that might be critical with regard to hemodynamics. RESULTS: It was found that in healthy people impedances of the aorta and the carotid artery decrease markedly with age especially during body growth. It was also found that impedances of the main arteries do not significantly change with heart rate, even if sharp changes in arterial distensibility are observed. With respect to optimal flow performance, it was found that scaling between diameters of branching arteries is generally close to optimality, while the corresponding length scaling is far from optimality. It was also found that the ascending aorta and aortic arch are among those arterial segments whose lengths are much smaller than the optimum values. An explanation is offered for the age associated elongation of the aorta in healthy people. CONCLUSIONS: In healthy subjects, the human arterial system continues to optimize its performance at least until the age of 60.

Effect of transverse aortic constriction on cardiac structure, function and gene expression in pregnant rats.

BACKGROUND: There is an increased risk of heart failure and pulmonary edema in pregnancies complicated by hypertensive disorders. However, in a previous study we found that pregnancy protects against fibrosis and preserves angiogenesis in a rat model of angiotensin II induced cardiac hypertrophy. In this study we test the hypothesis that pregnancy protects against negative effects of increased afterload. METHODS: Pregnant (gestational day 5.5-8.5) and non-pregnant Wistar rats were randomized to transverse aortic constriction (TAC) or sham surgery. After 14.2 ± 0.14 days echocardiography was performed. Aortic blood pressure and left ventricular (LV) pressure-volume loops were obtained using a conductance catheter. LV collagen content and cardiomyocyte circumference were measured. Myocardial gene expression was assessed by real-time polymerase chain reaction. RESULTS: Heart weight was increased by TAC (p<0.001) but not by pregnancy. Cardiac myocyte circumference was larger in pregnant compared to non-pregnant rats independent of TAC (p = 0.01), however TAC per se did not affect this parameter. Collagen content in LV myocardium was not affected by pregnancy or TAC. TAC increased stroke work more in pregnant rats (34.1 ± 2.4 vs 17.5 ± 2.4 mmHg/mL, p<0.001) than in non-pregnant (28.2 ± 1.7 vs 20.9 ± 1.5 mmHg/mL, p = 0.06). However, it did not lead to overt heart failure in any group. In pregnant rats, α-MHC gene expression was reduced by TAC. Increased in the expression of ß-MHC gene was higher in pregnant (5-fold) compared to non-pregnant rats (2-fold) after TAC (p = 0.001). Nine out of the 19 genes related to cardiac remodeling were affected by pregnancy independent of TAC. CONCLUSIONS: This study did not support the hypothesis that pregnancy is cardioprotective against the negative effects of increased afterload. Some differences in cardiac structure, function and gene expression between pregnant and non-pregnant rats following TAC indicated that afterload increase is less tolerated in pregnancy.

On-site education of VEGF-recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells.

Adult neovascularization relies on the recruitment of monocytes to the target organ or tumor and functioning therein as a paracrine accessory. The exact origins of the recruited monocytes and the mechanisms underlying their plasticity remain unclear. Using a VEGF-based transgenic system in which genetically tagged monocytes are conditionally summoned to the liver as part of a VEGF-initiated angiogenic program, we show that these recruited cells are derived from the abundant pool of circulating Ly6C(hi) monocytes. Remarkably, however, upon arrival at the VEGF-induced organ, but not the naive organ, monocytes undergo multiple phenotypic and functional changes, endowing them with enhanced proangiogenic capabilities and, importantly, with a markedly increased capacity to remodel existing small vessels into larger conduits. Notably, monocytes do not differentiate into long-lived macrophages, but rather appear as transient accessory cells. Results from transfers of presorted subpopulations and a novel tandem transfer strategy ruled out selective recruitment of a dedicated preexisting subpopulation or onsite selection, thereby reinforcing active reprogramming as the underlying mechanism for improved performance. Collectively, this study uncovered a novel function of VEGF, namely, on-site education of recruited "standard" monocytes to become angiogenic and arteriogenic professional cells, a finding that may also lend itself for a better design of angiogenic therapies.

Morphometric study of aortic wall parameters evolution in newborn and child.

The largest artery in the human body, intimately connected to the heart, aorta is usually regarded as the major source of oxygenated blood for the circulatory system. The three concentric layers, which surround the aortic lumen-the tunics intima, media and adventitia, transform the aorta in a large elastic duct, which is irregular calibrated according to its segments. The special aortic distensibility is facilitated by its elastic circumferential lamellar complex. Any disturbance of its structural components is able to interfere with its normal and vital activity. Our study intends to reveal that the development of elastic lamellae should be regarded not only as an indispensable step for the aortic wall configuration, but also like a process in a firm connection with the rest of aortic wall components. The transition from intrauterine life to a new stage of life, childhood, has to determine an adequate adaptation of almost all the components of aortic wall, in order to sustain a consistent pulsatile blood flow. Stereological quantitative analysis of thoracic aortic fragments prelevated from newborns and children was performed in order to estimate the dynamic of vascular wall increase. We first estimated the general configuration of the thoracic aortic wall, quantifying the principal constituents; the connective tissue profile, investigated through its main elements, collagen and elastic fibers, supports the idea that each type of fiber has a distinct evolution in different groups of ages and has to be correlated with their involvement in maintaining of the aortic wall mechanical properties. Elastic fibers percentage volume was increased in both examined groups, with a small difference reported in children aorta, while collagen fibers exhibit a slow increase in children aorta. Our morphometric quantitative assessment suggests that further studies have to draw of in a precisely manner the outline of the secretory well defined function of vascular smooth muscle cells; the elucidation of the manner in which the secretory pathway for each type of fiber becomes fully adapted to every stage of aortic development will allow a new perspective in aortic pathology.

Effects of taxifolin on the activity of angiotensin-converting enzyme and reactive oxygen and nitrogen species in the aorta of aging rats and rats treated with the nitric oxide synthase inhibitor and dexamethasone.

The action of taxifolin on the angiotensin-converting enzyme (ACE) and the formation of reactive oxygen and nitrogen species (ROS/RNS) in the aorta of aging rats and rats treated with nitric oxide synthase inhibitor (N ω-nitro-L-arginine methyl ester (L-NAME)) or dexamethasone have been studied. The ACE activity in aorta sections was determined by measuring the hydrolysis of hippuryl-L-histidyl-L-leucine, and the ROS/RNS production was measured by oxidation of dichlorodihydrofluorescein. It was shown that taxifolin at a dose of 30-100 µg/kg/day decreases the ACE activity in the aorta of aging rats and of rats treated with L-NAME or dexamethasone to the level of the ACE activity in young control rats. Taxifolin (100 µg/kg/day) was found to also reduce the amount of ROS/RNS in the aorta that increased as a result of L-NAME intake. L-NAME treatment increases the contribution of 5-lipoxygenase and NADPH oxidase to ROS/RNS production in the aorta, while taxifolin (100 µg/kg/day) decreases the contribution of these enzymes to the normal level.