Artery Growth Research Articles

OUTCOMES OF PALLIATIVE RIGHT VENTRICLE TO PULMONARY ARTERY CONNECTION FOR TETRALOGY OF FALLOT WITH PULMONARY ATRESIA AND MAPCAS

<h3>BACKGROUND</h3> Tetralogy of Fallot with pulmonary atresia with major aorto pulmonary artery collaterals (TOF-PA MAPCAS) is a rare and complex cyanotic congenital heart malformation with a high incidence of early mortality and morbidity. Different surgical interventions have been described including construction of a systemic to pulmonary artery shunt (Modified Blalock-Taussig shunt or central shunt) and unifocalization, however the perioperative mortality remains significant due to the high incidence of thrombosis, obstruction, and pulmonary artery (PA) distortion. Another alternative is a palliative right ventricle to pulmonary artery connection (RVPAC) to bring antegrade flow to diminutive PAs. The objective of our study was to evaluate the impact of RVPAC on mortality, survival, morbidity, PA growth and eligibility for biventricular repair. We believe that the RVPAC approach allows for better PA growth and obviates the need for a conduit at the time of complete repair. <h3>METHODS AND RESULTS</h3> We performed a retrospective single-institution study from January 2016 to March 2021 that included 15 consecutive patients diagnosed with TOF-PA MAPCAS who underwent an RVPAC at CHU Sainte-Justine as their initial palliation. Median age at palliation and complete repair was 18 (4 -100) and 309 (96 – 1044) days respectively. Mortality after a RVPAC was 0 % with a median hospital length of stay of 14,5 days (6 - 55), while the late interstage mortality rate was 0 %. Overall survival was 100 %. 9 patients (60%) had a biventricular repair, and 6 patients (40%) are awaiting repair. RVPAC allowed significant growth of the native pulmonary arteries with a mean Nakata index at CT scan of 70 ± 48,04 mm2/m2 before the RVPAC and 251 ± 121,05 mm2/m2 after (P = 0.001). 4 patients (44%) required reinterventions after completed repair by catheterization for stenotic pulmonary artery branches, while no patients required a late reoperation. 8 patients (53,33%) had embolization of collaterals and none required unifocalization. <h3>CONCLUSION</h3> This reproducible and safe technique allows for excellent growth of the PA tree. Biventricular repair was possible in most cases without the use of a conduit or unifocalization of collaterals. This technique appears to be suitable for any type of TOF-PA MAPCAS with confluent native branch pulmonary arteries.

Impact of Transcatheter Pulmonary Artery Intervention Following Superior Cavopulmonary Connection on Pulmonary Artery Growth.

Balloon and stent angioplasty of the pulmonary arteries (PAs) are frequently performed following superior cavopulmonary connection (SCPC), not only to normalize the caliber of the affected PA but also in hopes of maximizing downstream growth over time. There are limited data on the impact on subsequent PA growth prior to total cavopulmonary connection (TCPC). A single-center, retrospective cohort study was performed on children who underwent transcatheter (TC) PA intervention following SCPC between January 1, 2010, and December 31, 2018. Growth of treated and contralateral PAs was measured at the lobar bifurcation (distal branch PA [DBPA]) and in the proximal lower lobe (lower lobe branch [LLB]) on serial angiograms. Growth rate was evaluated using a mixed-effect model clustered by individual patient with an interaction term for treated PA and time to evaluate for differential growth rates between treated and contralateral PAs. Thirty-five patients underwent TC PA intervention following SCPC, at a median of 70 days (interquartile range: 19-297 days) postoperatively. Significant growth was seen at both DBPA and LLB for raw (0.8 mm/year, 95% CI: 0.6-1.0, P < .001 for both) and body surface area (BSA) adjusted measures (8.4mm/m2/year, 95% CI: 5.6-11.2, P < .001; 7.9 mm/m2/year, 95% CI: 5.5-10.2, P < .001). The growth rate of the treated vessel was not significantly different from that of the contralateral vessel at the DBPA or LLB positions for raw (P = .71, .70) or BSA-adjusted measurements (P = .86, .64). Transcatheter PA intervention was associated with normal distal PA growth rate relative to the untreated side.

Outcome of ductus arteriosus stenting including vertical tubular and convoluted tortuous ducts with emphasis on technical considerations

BackgroundDuctal stenting is the preferred method of securing adequate pulmonary blood flow in patients with duct-dependent pulmonary circulation. The main limitation in most centers is the difficult vertical tubular or convoluted ducts that represent real challenges to interventional pediatric cardiologists. We present our experience in patent ductus arteriosus (PDA) stenting with some technical tips to overcome difficulties, especially in stenting tortuous or long tubular ducts. This study was conducted on all patients with cyanotic congenital heart disease who underwent PDA stenting between January 2011 and December 2018.ResultsWe attempted to stent the PDA in 43 patients, with a success rate of 93% (40 patients) and only one procedural mortality. There was also one stent migration that needed to be treated with urgent surgery. Three-fourths of the patients had difficult ductal morphology and origin. One stent was used to cover the PDA in 27 patients (62.8%), two stents were used in 13 (30.2%), and three stents were used in 2 patients (4.6%). In-stent stenosis rate was 12.5% (5 patients) and the development of progressive left pulmonary artery stenosis was seen in two patients (5%). Pulmonary artery growth was adequate in all patients.ConclusionsPDA stenting is an effective method of palliation for patients with duct-dependent pulmonary circulation. It has low morbidity and mortality rates. Stenting difficult ducts have become more feasible with evolving materials and techniques.

Primary central pulmonary artery plasty for right atrial isomerism with pulmonary coarctation.

Patients with unbalanced pulmonary artery growth resulting from pulmonary coarctation are considered unsuitable candidates for the Fontan procedure. Particularly, patients with right isomerism pose a challenge. We aimed to investigate the use of primary central pulmonary artery plasty at initial palliation in patients with right isomerism. We recruited 34 right isomerism patients with pulmonary atresia and pulmonary coarctation who underwent modified Blalock-Taussig shunt with or without primary central pulmonary artery plasty between 1998 and 2014. We classified them into the primary central pulmonary artery plasty (group P) and no primary central pulmonary artery plasty (group N) groups. We retrospectively analyzed reintervention for pulmonary artery after initial palliation, difference in size between the left and right pulmonary arteries, overall survival, success of the Fontan procedure. The group P and group N included 25 and 9 patients, respectively. Five (20%) and six (67%) patients in group P and group N, respectively, required reintervention for pulmonary artery after initial palliation (p = 0.017). No patient underwent reintervention for the pulmonary artery before bidirectional cavopulmonary shunt in group P. There was a significant difference in the bilateral pulmonary artery size balance between the groups before bidirectional cavopulmonary shunt (p = 0.041). The two-lung Fontan procedure was successful in 14 (56%) and 1 (11%) patient in group P and group N. Primary central pulmonary artery plasty may contribute toward improving the balance in the size of the PA and preclude the need for reintervention for PA.

Comparison of Patent Ductus Arteriosus Stent and Blalock-Taussig Shunt as Palliation for Neonates with Sole Source Ductal-Dependent Pulmonary Blood Flow: Results from the Congenital Catheterization Research Collaborative.

Patent ductus arteriosus (PDA) stenting is an accepted method for securing pulmonary blood flow in cyanotic neonates. In neonates with pulmonary atresia and single source ductal-dependent pulmonary blood flow (SSPBF), PDA stenting remains controversial. We sought to evaluate outcomes in neonates with SSPBF, comparing PDA stenting and surgical Blalock-Taussig shunt (BTS). Neonates with SSPBF who underwent PDA stenting or BTS at the four centers of the Congenital Catheterization Research Collaborative from January 2008 to December 2015 were retrospectively reviewed. Reintervention on the BTS or PDA stent prior to planned surgical repair served as the primary endpoint. Additional analyses of peri-procedural complications, interventions, and pulmonary artery growth were performed. A propensity score was utilized to adjust for differences in factors. Thirty-five patients with PDA stents and 156 patients with BTS were included. The cohorts had similar baseline characteristics, procedural complications, and mortality. Interstage reintervention rates were higher in the PDA stent cohort (48.6% vs. 15.4%, p < 0.001).

Novel technique of achieving hemodynamic stability during systemic to pulmonary artery shunt.

Historically, the Blalock Taussig (BT) shunt has been an off-pump procedure. For the last two decades, the number of BT shunt operations has come down globally with the adoption of neonatal early corrective surgery. BT shunts are still performed for augmentation of pulmonary arterial (PA) growth or as a part of univentricular palliation. Many infants do not tolerate PA branch clamping while undergoing the graft to PA anastomosis, necessitating institution of cardiopulmonary bypass (CPB). Since the threshold to go on CPB for shunt placement is quite low at most institutions, our technical modification described can avoid deleterious effect of CPB. Our point of interest is to maintain lung perfusion by adopting few principles of off-pump coronary artery bypass surgery.

Neonatal or infantile palliation for Tetralogy of Fallot with or without pulmonary atresia: Modified Blalock–Taussig shunt versus restrictive right ventricle to pulmonary artery connection. A 20-year experience

To compare mortality, morbidity and efficiency of modified Blalock–Taussig shunt (mBTS) versus restrictive right ventricle to pulmonary artery connection (RVPAc) in patients with Tetralogy of Fallot (TOF) and TOF with pulmonary atresia (TOF-PA). We performed a monocentric retrospective review of 198 patients (93 TOF and 105 TOF-PA) who had palliation between 1996 to 2016 in their first year of life. Patients with Major aorto-pulmonary collaterals were excluded. Median follow-up was 11.0 [95% CI: 5.8–16.2] years after palliation. Five patients were lost at the follow-up. Ninety-five patients underwent mBTS, and 103 had an RVPAc. Nakata index before palliation was 129 (80–170) mm 2 /m 2 in mBTS group and 100 (71–146) mm 2 /m 2 in RVPAc group ( P = 0.001). Weight at palliation was similar between mBTS and RVPAc patients ( P = 0.1). Age at the palliation was 12 days (7–24.7) in RVPAc group and 21 days (8–87.5) in mBTS group ( P = 0.0002). One hundred and seventy-five patients underwent repair and 5 are waiting for it. Among them 39 necessitated a repair with a pulmonary valve conduit (23 mBTS and 16 RVPAc P = 0.004). Two patients were unsuitable for repair. Eleven patients died before repair (5.7%). There was no difference in mortality rate regarding the type of palliation ( P = 0.92) or the anatomical group ( P = 0.76). Interstage reintervention before repair was n = 37 (20%). Thirty-three were surgical and four were percutaneous. No difference in reintervention rate between RVPAc or mBTS regarding the age, the weight at palliation or the anatomical group ( P = 0.56). The delay between the palliation and the complete repair was shorter in RVPAc [12.3 (6.3–37.9) months versus 6.5 (4.9–10.3) months for mBTS ( P < 0.01)]. RVPAc provide a better and a faster pulmonary artery growth in our population. It led us to limit the use of RVPAc conduit at the repair. We found no significant difference between mBTS and RVPAc for mortality and interstage reintervention.

Endothelial Hyaluronan Synthase 3 Augments Postischemic Arteriogenesis Through CD44/eNOS Signaling.

Objective: The dominant driver of arteriogenesis is elevated shear stress sensed by the endothelial glycocalyx thereby promoting arterial outward remodeling. Hyaluronan, a critical component of the endothelial glycocalyx, is synthesized by 3 HAS isoenzymes (hyaluronan synthases 1-3) at the plasma membrane. Considering further the importance of HAS3 for smooth muscle cell and immune cell functions we aimed to evaluate its role in collateral artery growth. Approach and Results: Male Has3-deficient (Has3-KO) mice were subjected to hindlimb ischemia. Blood perfusion was monitored by laser Doppler perfusion imaging and endothelial function was assessed by measurement of flow-mediated dilation in vivo. Collateral remodeling was monitored by high resolution magnetic resonance angiography. A neutralizing antibody against CD44 (clone KM201) was injected intraperitoneally to analyze hyaluronan signaling in vivo. After hindlimb ischemia, Has3-KO mice showed a reduced arteriogenic response with decreased collateral remodeling and impaired perfusion recovery. While postischemic leukocyte infiltration was unaffected, a diminished flow-mediated dilation pointed towards an impaired endothelial cell function. Indeed, endothelial AKT (protein kinase B)-dependent eNOS (endothelial nitric oxide synthase) phosphorylation at Ser1177 was substantially reduced in Has3-KO thigh muscles. Endothelial-specific Has3-KO mice mimicked the hindlimb ischemia-induced phenotype of impaired perfusion recovery as observed in global Has3-deficiency. Mechanistically, blocking selectively the hyaluronan binding site of CD44 reduced flow-mediated dilation, thereby suggesting hyaluronan signaling through CD44 as the underlying signaling pathway. Conclusions: In summary, HAS3 contributes to arteriogenesis in hindlimb ischemia by hyaluronan/CD44-mediated stimulation of eNOS phosphorylation at Ser1177. Thus, strategies augmenting endothelial HAS3 or CD44 could be envisioned to enhance vascularization under pathological conditions.

Dach1 Extends Artery Networks and Protects Against Cardiac Injury.

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Shear stress related plaque progression in human coronary arteries is dependent on sex and age

Background and Aims: Endothelial shear stress (ESS) is known to play a critical role in coronary atherosclerosis progression. Clinical atherosclerosis manifestations are different in women compared to men. Knowledge is lacking on sex-related differences in ESS distribution or ESS-related plaque progression. Aim of this study was to investigate differences in ESS and ESS-related plaque growth in coronary arteries of men compared to women.

Biomechanical consequences of compromised elastic fiber integrity and matrix cross-linking on abdominal aortic aneurysmal enlargement

Abdominal aortic aneurysms (AAAs) are characterized histopathologically by compromised elastic fiber integrity, lost smooth muscle cells or their function, and remodeled collagen. We used a recently introduced mouse model of AAAs that combines enzymatic degradation of elastic fibers and blocking of lysyl oxidase, and thus matrix cross-linking, to study progressive dilatation of the infrarenal abdominal aorta, including development of intraluminal thrombus. We quantified changes in biomaterial properties and biomechanical functionality within the aneurysmal segment as a function of time of enlargement and degree of thrombosis. Towards this end, we combined multi-modality imaging with state-of-the art biomechanical testing and histology to quantify regional heterogeneities for the first time and we used a computational model of arterial growth and remodeling to test multiple hypotheses, suggested by the data, regarding the degree of lost elastin, accumulation of glycosaminoglycans, and rates of collagen turnover. We found that standard histopathological findings can be misleading, while combining advanced experimental and computational methods revealed that glycosaminoglycan accumulation is pathologic, not adaptive, and that heightened collagen deposition is ineffective if not cross-linked. In conclusion, loss of elastic fiber integrity can be a strong initiator of aortic aneurysms, but it is the rate and effectiveness of fibrillar collagen remodeling that dictates enlargement. Statement of SignificancePrecise mechanisms by which abdominal aortic aneurysms enlarge remain unclear, but a recent elastase plus β-aminopropionitrile mouse model provides new insight into disease progression. As in the human condition, the aortic degeneration and adverse remodeling are highly heterogeneous in this model. Our multi-modality experiments quantify and contrast the heterogeneities in geometry and biomaterial properties, and our computational modeling shows that standard histopathology can be misleading. Neither accumulating glycosaminoglycans nor frustrated collagen synthesis slow disease progression, thus highlighting the importance of stimulating adaptive collagen remodeling to limit lesion enlargement.

Statins Mitigate Stress-Related Vascular Aging and Atherosclerosis in apoE-Deficient Mice Fed High Fat-Diet: The Role of Glucagon-Like Peptide-1/Adiponectin Axis.

ObjectivesExposure to chronic psychosocial stress is a risk factor for atherosclerotic cardiovascular diseases. Given that the 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitor statins prevent atherogenesis, we evaluated whether pitavastatin prevents chronic stress- and high fat diet-induced vascular senescence and atherogenesis in apolipoprotein E-deficient (ApoE–/–) mice, with a special focus on glucagon-like peptide-1 (GLP-1)/adiponectin (APN) axis.Methods and Results6-week-old ApoE–/– mice loaded a high-fat diet were randomly assigned into non-stress (n = 12) and stress (n = 13) groups for 12 weeks. Non-stress control mice were left undisturbed. Chronic stress accelerated high fat diet-induce arterial senescence and atherosclerotic plaque growth. The chronic stress lowered the levels of circulating GLP-1 as well as adipose and plasma APN. As compared with the stress alone mice, the pitavastatin-treated mice had reduced macrophage infiltration, elastin fragments, and increased plaque collagen volume, and lowered levels of osteopontin, toll-like receptor-2/-4, macrophage chemoattractant protein-1, C-X-C chemokine receptor-4, p47phox, p47phox, gp91phox, cathepsins S, p16, and p21, mRNAs and/or proteins. Pitavastatin increased plasma GLP-1 and APN levels and suppressed matrix metalloproteinase-2/-9 gene expressions and activities in the aortas. Finally, the protective effect of pitavastatin was abrogated by APN blocking.ConclusionThese findings suggested that the pitavastatin-mediated pleiotropic vasculoprotective effects are likely attributable, at least in part, to the elevation of GLP-1 and APN levels and the inhibition of diet-induced plaque inflammation, oxidative stress, and proteolysis in ApoE–/– mice received chronic stress conditions.

Plasticity and Enzymatic Degradation Coupled With Volumetric Growth in Pulmonary Hypertension Progression.

Pulmonary hypertension (PH) is one of the least understood and highly elusive cardiovascular conditions associated with elevated pulmonary arterial pressure. Although the disease mechanisms are not completely understood, evidence has accumulated from human and animal studies that irreversible processes of pulmonary arterial wall damage, compensated by stress-mediated growth, play critical roles in eliciting the mechanisms of disease progression. The aim of this study is to develop a thermodynamic modeling structure of the pulmonary artery to consider coupled plastic-degradation-growth irreversible processes to investigate the mechanical roles of the dissipative phenomena in the disease progression. The proposed model performs a model parameter study of plastic deformation and degradation processes coupled with dissipative growth subjected to elevated pulmonary arterial pressure and computationally generates in silico simulations of PH progression using the clinical features of PH, found in human morphological and mechanical data. The results show that considering plastic deformation can provide a much better fitting of the ex vivo inflation tests than a widely used pure hyperelastic model in higher pressure conditions. In addition, the parameter sensitivity study illustrates that arterial damage and growth cause the increased stiffness, and the full simulation (combining elastic-plastic-degradation-growth models) reveals a key postpathological recovery process of compensating vessel damage by vascular adaptation by reducing the rate of vessel dilation and mediating vascular wall stress. Finally, the simulation results of luminal enlargement, arterial thickening, and arterial stiffness for an anisotropic growth are found to be close to the values from the literature.

Irradiation Accelerates Plaque Formation and Cellular Senescence in Flow-Altered Carotid Arteries of Apolipoprotein E Knock-Out Mice.

BackgroundChronic inflammation through cellular senescence, known as the senescence‐associated secretory phenotype, is a mechanism of various organ diseases, including atherosclerosis. Particularly, ionizing radiation (IR) contributes to cellular senescence by causing DNA damage. Although previous clinical studies have demonstrated that radiotherapy causes atherosclerosis as a long‐term side effect, the detailed mechanism is unclear. This study was conducted to investigate the relationship between radiation‐induced atherosclerosis and senescence‐associated secretory phenotype in murine carotid arteries.Methods and ResultsPartial ligation of the left carotid artery branches in 9‐week‐old male apolipoprotein E‐deficient mice was performed to induce atherosclerosis. The mice received total body irradiation at a dose of 6 Gy using gamma rays at 2 weeks post operation. We compared the samples collected 4 weeks after IR with unirradiated control samples. The IR and control groups presented pathologically progressive lesions in 90.9% and 72.3% of mice, respectively. Plaque volume, macrophage accumulation, and phenotype switching of vascular smooth muscle cells were advanced in the IR group. Irradiated samples showed increased persistent DNA damage response (53BP1 [p53 binding protein 1]), upregulated cyclin‐dependent kinase inhibitors (p16INK4a and p21), and elevated inflammatory chemokines expression (monocyte chemotactic protein‐1, keratinocyte‐derived chemokine, and macrophage inflammatory protein 2).ConclusionsIR promoted plaque growth in murine carotid arteries. Our findings support the possibility that senescence‐associated secretory phenotype aggravates atherogenesis in irradiated artery. This mice model might contribute to mechanism elucidation of radiation‐induced atherosclerosis.

Normalization of wall shear stress as a physiological mechanism for regulating maternal uterine artery expansive remodeling during pregnancy.

Outward remodeling of the maternal uterine circulation during pregnancy is essential for normal uteroplacental perfusion and pregnancy outcome. The physiological mechanism by which this process is regulated is unknown; we hypothesized that it involved the normalization of wall shear stress (WSS). Pregnant Sprague–Dawley rats underwent unilateral ligation of the main uterine artery and vein at the cervical end of the uterus on gestational day 10, thus restricting inflow/outflow of blood into that uterine horn to a single point at the ovarian end; the contralateral sham‐operated side provided an internal control. This procedure alters uterine hemodynamics by increasing WSS, since the entire uterine horn is supplied by one rather than two vessels. Arterial diameter and blood flow velocity values were measured by intravital ultrasonographic pulse‐wave Doppler on gestational day 20 and used to calculate WSS. Although both ovarian artery lumen diameter and blood velocity increased, WSS was similar in both horns. These data support the concept that increased WSS secondary to hemochorial placentation is the primary physiological stimulus for uterine vascular remodeling and that its normalization may be the primary mechanism that regulates the extent of arterial circumferential growth required to maintain placental perfusion. We further hypothesize that shallow spiral artery invasion, such as occurs in preeclampsia, limits the increase in upstream shear stress and results in attenuated remodeling and placental under‐perfusion.

Duct-dependent cyanotic neonates with patent ductus arteriosus stenting pose a unique challenge for the next stage of surgical intervention

Objective To study the role of patent ductus arteriosus (PDA) stenting in the management of single-ventricle patients and the surgical difficulties facing the surgeons in the next stages of surgical procedures. Background Thirty consecutive neonates with cyanotic duct-dependent lesions were initially palliated with (PDA) stenting in our center. Eighteen of them had undergone one or more surgical procedures. We retrospectively assessed the indexed growth of pulmonary arteries (PA) over a period of time and the requirement of further rehabilitation of PAs in these patients. Patients and methods From January 2014 to December 2018, 30 neonates with cyanotic congenital heart diseases underwent PDA stenting as initial palliation; 60% were ventilated before the procedure, which resulted in 100% success. All patients were followed up regularly by monitoring of PA size imaging. Eighteen patients of this group underwent further surgical procedures. Results Ninety percent of the neonates had stenosis of the PA branches before PDA stenting. The indexed PA branch size was significantly smaller, which increased after stenting of PDA. At the time of the next surgical procedures (Glenn, etc.), stent division/ligation was required in addition to PA plasty in 90% of patients. Conclusions PDA stenting provides efficient palliation in cyanotic neonates. Despite the origin of stenosis, the stent allowed growth in the size of both PAs. However, the majority required surgical augmentation and further stenting of PAs in the mid-term follow-up.

Mechanical role of intraluminal thrombus in aneurysm growth: A computational study.

Models that seek to improve our current understanding of biochemical processes and predict disease progression have been increasingly in use over the last decades. Recently, we proposed a finite element implementation of arterial wall growth and remodeling with application to abdominal aortic aneurysms (AAAs). The study focused on changes within the aortic wall and did not include the complex role of intraluminal thrombus (ILT) during the AAA evolution. Thus, in this work, we extend the model with a gradual deposition of ILT and its mechanical influence on AAA growth. Despite neglecting the increased biochemical activity due to the presence of a proteolytically active luminal layer of ILT, and thus underestimating rupture risk potential, we show that ILT helps to slow down the growth of the aneurysm in the axial direction by redirecting blood pressure loading from the axial-radial plane to predominately radial direction. This very likely lowers rupture potential. We also show that the ratio of ILT volume to volume sac is an important factor in AAA stabilization and that fully thrombosed aneurysms could stabilize quicker and at smaller maximum diameters compared to partially thrombosed ones. Furthermore, we show that ILT formation and the associated mural stress decrease negatively impact the wall constituent production and thickness. Although further studies that include increased biochemical degradation of the wall after the formation of ILT and ILT deposition based on hemodynamics are needed, the present findings highlight the dual role an ILT plays during AAA progression.

Architecture-Dependent Mechano-Adaptation in Single Vascular Smooth Muscle Cells.

Arteries grow and remodel following mechanical perturbation. Vascular smooth muscle cells (VSMCs) within the artery undergo hyperplasia, hypertrophy, or change their contractility following sustained changes in loading. Experimental evidence in vivo and in vitro suggests that VSMCs grow and remodel to maintain a constant transmural stress, or "target" stress. This behavior is often described using a stress-dependent finite growth framework. Typically, computational models of arterial growth and remodeling account for VSMC behavior in a constrained mixture formulation that incorporates behavior of each component of the artery. However, these models do not account for differential VSMC architecture observed in situ, which may significantly influence growth and remodeling behavior. Here, we used cellular microbiaxial stretching (CμBS) to characterize how VSMCs with different cytoskeletal architectures respond to a sustained step change in strain. We find that VSMC F-actin architecture becomes more aligned following stretch and retains this alignment after 24 h. Further, we find that VSMC stress magnitude depends on cellular architecture. Qualitatively, however, stress behavior following stretch is consistent across cell architectures-stress increases following stretch and returns to prestretch magnitudes after 24 h. Finally, we formulated an architecture-dependent targeted growth law that accounts for experimentally measured cytoskeletal alignment and attributes stress evolution to individual fiber growth and find that this model robustly captures long-term stress evolution in single VSMCs. These results suggest that VSMC mechano-adaptation depends on cellular architecture, which has implications for growth and remodeling in regions of arteries with differential architecture, such as at bifurcations.

Assessing Early Cardiac Outflow Tract Adaptive Responses Through Combined Experimental-Computational Manipulations.

Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general acknowledgement of a hemodynamic-malformation link, the direct correlation between hemodynamics and PAA morphogenesis remains poorly understood. The elusiveness is largely due to difficulty in performing isolated hemodynamic perturbations and quantifying changes in-vivo. Previous in-vivo arch artery occlusion/ablation experiments either did not isolate the effects of hemodynamics, did not analyze the results in a 3D context or did not consider the effects of varying degrees of occlusion. Here, we overcome these limitations by combining minimally invasive occlusion experiments in the avian embryo with 3D anatomical models of development and in-silico testing of experimental phenomenon. We detail morphological and hemodynamic changes 24hours post vessel occlusion. 3D anatomical models showed that occlusion geometries had more circular cross-sectional areas and more elongated arches than their control counterparts. Computational fluid dynamics revealed a marked change in wall shear stress-morphology trends. Instantaneous (in-silico) occlusion models provided mechanistic insights into the dynamic vessel adaptation process, predicting pressure-area trends for a number of experimental occlusion arches. We follow the propagation of small defects in a single embryo Hamburger Hamilton (HH) Stage 18 embryo to a more serious defect in an HH29 embryo. Results demonstrate that hemodynamic perturbation of the presumptive aortic arch, through varying degrees of vessel occlusion, overrides natural growth mechanisms and prevents it from becoming the dominant arch of the aorta.

Role of TRPV4 channel in vasodilation and neovascularization

The transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca2+ -permeable nonselective cation channel, is widely distributed in the circulatory system, particularly in vascular endothelial cells (ECs) and smooth muscle cells (SMCs). The TRPV4 channel is activated by various endogenous and exogenous stimuli, including shear stress, low intravascular pressure, and arachidonic acid. TRPV4 has a role in mediating vascular tone and arterial blood pressure. The activation of the TRPV4 channel induces Ca2+ influx, thereby resulting in endothelium-dependent hyperpolarization and SMC relaxation through SKCa and IKCa activation on ECs or through BKCa activation on SMCs. Ca2+ binds to calmodulin, which leads to the production of nitric oxide, causing vasodilation. Furthermore, the TRPV4 channel plays an important role in angiogenesis and arteriogenesis and is critical for tumor angiogenesis and growth, since it promotes or inhibits the development of various types of cancer. The TRPV4 channel is involved in the active growth of collateral arteries induced by flow shear stress, which makes it a promising therapeutic target in the occlusion or stenosis of the main arteries. In this review, we explore the role and the potential mechanism of action of the TRPV4 channel in the regulation of vascular tone and in the induction of neovascularization to provide a reference for future research.