W Robert Taylor

Publications of W Robert Taylor

• GROWTH AND REGRESSION OF VASCULATURE IN HEALTHY AND DIABETIC MICE AFTER HIND LIMB ISCHEMIA.

  Authors: Natalia Landázuri, Giji Joseph, Robert E Guldberg, W Robert Taylor

  American journal of physiology. Regulatory, integrative and comparative physiology. 05/2012;

  The formation of vascular networks during embryogenesis and early stages of development encompasses complex and tightly regulated growth of blood vessels, followed by maturation of some vessels, andThe formation of vascular networks during embryogenesis and early stages of development encompasses complex and tightly regulated growth of blood vessels, followed by maturation of some vessels, and spatially controlled disconnection and pruning of others. The adult vasculature, while more quiescent, is also capable of adapting to changing physiological conditions by remodeling blood vessels. Numerous studies have focused on understanding key factors that drive vessel growth in the adult in response to ischemic injury. However, little is known about the extent of vessel rarefaction and its potential contribution to the final outcome of vascular recovery. We addressed this topic by characterizing the endogenous phases of vascular repair in a mouse model of hind limb ischemia. We showed that this process is biphasic. It encompasses an initial rapid phase of vessel growth, followed by a later phase of vessel rarefaction. In healthy mice, this process resulted in partial recovery of perfusion, and completely restored the ability of mice to run voluntarily. Given that the ability to revascularize can be compromised by a cardiovascular risk factor such as diabetes, we also examined vascular repair in diabetic mice. We found that paradoxically, both the initial growth and subsequent regression of collateral vessels were more pronounced in the setting of diabetes, and resulted in impaired recovery of perfusion and impaired functional status. In conclusion, our findings demonstrate that the formation of functional collateral vessels in the hind limb requires vessel growth and subsequent vessel rarefaction. In the setting of diabetes, the physiologic defect was not in the initial formation of vessels but rather in the inability to sustain newly formed vessels.

• Ultrasound Imaging of Oxidative Stress In Vivo with Chemically-Generated Gas Microbubbles.

  Authors: John Kangchun Perng, Seungjun Lee, Kousik Kundu, Charles F Caskey, Sarah F Knight, Sarp Satir, Katherine W Ferrara, W Robert Taylor, F Levent Degertekin, Daniel Sorescu, Niren Murthy

  Annals of biomedical engineering. 05/2012;

  Ultrasound contrast agents (UCAs) have tremendous potential for in vivo molecular imaging because of their high sensitivity. However, the diagnostic potential of UCAs has been difficult to exploitUltrasound contrast agents (UCAs) have tremendous potential for in vivo molecular imaging because of their high sensitivity. However, the diagnostic potential of UCAs has been difficult to exploit because current UCAs are based on pre-formed microbubbles, which can only detect cell surface receptors. Here, we demonstrate that chemical reactions that generate gas forming molecules can be used to perform molecular imaging by ultrasound in vivo. This new approach was demonstrated by imaging reactive oxygen species in vivo with allylhydrazine, a liquid compound that is converted into nitrogen and propylene gas after reacting with radical oxidants. We demonstrate that allylhydrazine encapsulated within liposomes can detect a 10 micromolar concentration of radical oxidants by ultrasound, and can image oxidative stress in mice, induced by lipopolysaccharide, using a clinical ultrasound system. We anticipate numerous applications of chemically-generated microbubbles for molecular imaging by ultrasound, given ultrasound's ability to detect small increments above the gas saturation limit, its spatial resolution and widespread clinical use.

• Reactive Oxygen Species Regulate Osteopontin Expression in a Murine Model of Postischemic Neovascularization.

  Authors: Alicia N Lyle, Giji Joseph, Aaron E Fan, Daiana Weiss, Natalia Landázuri, W Robert Taylor

  Arteriosclerosis, thrombosis, and vascular biology. 04/2012;

  OBJECTIVE: Previous findings from our laboratory demonstrated that neovascularization was impaired in osteopontin (OPN) knockout animals. However, the mechanisms responsible for the regulation of OPNOBJECTIVE: Previous findings from our laboratory demonstrated that neovascularization was impaired in osteopontin (OPN) knockout animals. However, the mechanisms responsible for the regulation of OPN expression in the setting of ischemia remain undefined. Therefore, we sought to determine whether OPN is upregulated in response to ischemia and hypothesized that hydrogen peroxide (H(2)O(2)) is a critical component of the signaling mechanism by which OPN expression is upregulated in response to ischemia in vivo. METHODS AND RESULTS: To determine whether ischemic injury upregulates OPN, we used a murine model of hindlimb ischemia. Femoral artery ligation in C57Bl/6 mice significantly increased OPN expression and H(2)O(2) production. Infusion of C57Bl/6 mice with polyethylene glycol-catalase (10 000 U/kg per day) or the use of transgenic mice with smooth muscle cell-specific catalase overexpression blunted ischemia-induced OPN, suggesting ischemia-induced OPN expression is H(2)O(2) dependent. Decreased H(2)O(2)-mediated OPN blunted reperfusion and collateral formation in vivo. In contrast, the overexpression of OPN using lentivirus restored neovascularization. CONCLUSIONS: Scavenging H(2)O(2) blocks ischemia-induced OPN expression, providing evidence that ischemia-induced OPN expression is H(2)O(2) dependent. Decreased OPN expression impaired neovascularization, whereas overexpression of OPN increased angiogenesis, supporting our hypothesis that OPN is a critical mediator of postischemic neovascularization and a potential novel therapeutic target for inducing new vessel growth.

• Folate Receptor-Targeted Antioxidant Therapy Ameliorates Renal Ischemia-Reperfusion Injury.

  Authors: Sarah F Knight, Kousik Kundu, Giji Joseph, Sergey Dikalov, Daiana Weiss, Niren Murthy, W Robert Taylor

  Journal of the American Society of Nephrology : JASN. 01/2012;

  Antioxidant therapy can protect against ischemic injury, but the inability to selectively target the kidney would require extremely high doses to achieve effective local concentrations of drug. Here,Antioxidant therapy can protect against ischemic injury, but the inability to selectively target the kidney would require extremely high doses to achieve effective local concentrations of drug. Here, we developed a directed therapeutic that specifically targets an antioxidant to renal proximal tubule cells via the folate receptor. Because a local increase in superoxide contributes to renal ischemic injury, we created the folate-antioxidant conjugate 4-hydroxy-Tempo (tempol)-folate to target folate receptors, which are highly expressed in the proximal tubule. Dihydroethidium high-performance liquid chromatography demonstrated that conjugated tempol retained its efficacy to scavenge superoxide in proximal tubule cells. In a mouse model of renal ischemia-reperfusion injury, tempol-folate reduced renal superoxide levels more effectively than tempol alone. Furthermore, electron spin resonance revealed the successful targeting of the tempol-folate conjugate to the kidney and other tissues expressing folate receptors. Administration of tempol-folate protected the renal function of mice after ischemia-reperfusion injury and inhibited infiltration of macrophages. In conclusion, kidney-specific targeting of an antioxidant has therapeutic potential to prevent renal ischemic injury. Conjugation of other pharmaceuticals to folate may also facilitate the development of treatments for other kidney diseases.

• The changing face and abbreviated lives of bone marrow cells in the heart.

  Authors: Scott T Robinson, Natalia Landázuri, W Robert Taylor

  Arteriosclerosis, thrombosis, and vascular biology. 01/2012; 32(1):1-2.

• Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis.

  Authors: Omar Saeed, Fumiyuki Otsuka, Rohini Polavarapu, Vinit Karmali, Daiana Weiss, Talina Davis, Brad Rostad, Kimberly Pachura, Lila Adams, John Elliott, W Robert Taylor, Jagat Narula, Frank Kolodgie, Renu Virmani, Charles C Hong, Aloke V Finn

  Arteriosclerosis, thrombosis, and vascular biology. 11/2011; 32(2):299-307.

  We recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. InWe recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis. To suppress hepcidin, increase expression of the iron exporter ferroportin, and reduce macrophage intracellular iron, we used a small molecule inhibitor of bone morphogenetic protein (BMP) signaling, LDN 193189 (LDN). LDN (10 mg/kg IP b.i.d.) was administered to mice, and its effects on atherosclerosis, intracellular iron, oxidative stress, lipid efflux, and foam cell formation were measured in plaques and peritoneal macrophages. Long-term LDN administration to apolipoprotein E-/- mice increased ABCA1 immunoreactivity within intraplaque macrophages by 3.7-fold (n=8; P=0.03), reduced Oil Red O-positive lipid area by 50% (n=8; P=0.02), and decreased total plaque area by 43% (n=8; P=0.001). LDN suppressed liver hepcidin transcription and increased macrophage ferroportin, lowering intracellular iron and hydrogen peroxide production. LDN treatment increased macrophage ABCA1 and ABCG1 expression, significantly raised cholesterol efflux to ApoA-1, and decreased foam cell formation. All preceding LDN-induced effects on cholesterol efflux were reversed by exogenous hepcidin administration, suggesting modulation of intracellular iron levels within macrophages as the mechanism by which LDN triggers these effects. These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.

• Redox signaling in an in vivo murine model of low magnitude oscillatory wall shear stress.

  Authors: Nick J Willett, Kousik Kundu, Sarah F Knight, Sergey Dikalov, Niren Murthy, W Robert Taylor

  Antioxidants & redox signaling. 09/2011; 15(5):1369-78.

  Wall Shear Stress (WSS) has been identified as an important factor in the pathogenesis of atherosclerosis. We utilized a novel murine aortic coarctation model to acutely create a region of lowWall Shear Stress (WSS) has been identified as an important factor in the pathogenesis of atherosclerosis. We utilized a novel murine aortic coarctation model to acutely create a region of low magnitude oscillatory WSS in vivo. We employed this model to test the hypothesis that acute changes in WSS in vivo induce upregulation of inflammatory proteins, mediated by reactive oxygen species (ROS). Superoxide generation and VCAM-1 expression both increased in regions of low magnitude oscillatory WSS. WSS-dependent superoxide formation was attenuated by tempol treatment, but was unchanged in p47 phox knockout (ko) mice. However, in both the p47 phox ko mice and the tempol-treated mice, low magnitude oscillatory WSS produced an increase in VCAM-1 expression comparable to control mice. Additionally, this same VCAM-1 expression was observed in ebselen-treated mice and catalase overexpressing mice. These results suggest that although the redox state is important to the overall pathogenesis of atherosclerosis, the initial WSS-dependent inflammatory response leading to lesion localization is not dependent on ROS.

• A clinical commentary on the article "N-acetylglucosamine conjugated to nanoparticles enhances myocyte uptake and improves delivery of a small molecule p38 inhibitor for post-infarct healing" : N-acetylglucosamine conjugated nanoparticles: translational opportunities and barriers.

  Authors: Rebecca D Levit, W Robert Taylor

  Journal of cardiovascular translational research. 08/2011; 4(5):644-5.

  Targeting drugs and nanoparticles to cardiomyocytes has been an elusive challenge. Cardiomyocytes are inherently non-phagocytic and their environment is subjected to contractile forces which tend toTargeting drugs and nanoparticles to cardiomyocytes has been an elusive challenge. Cardiomyocytes are inherently non-phagocytic and their environment is subjected to contractile forces which tend to expel injected and catheter-delivered drugs. In this issue, a novel-targeting strategy, N-acetyl-glucosamine (GlcNAc) coating, is shown to enhance cardiomyocyte nanoparticle uptake both in vitro and in vivo. Many effective and proven therapies for myocardial infarction are in clinical use thus raising the bar for the translation of new technologies. Nevertheless, GlcNAc targeting represents a promising approach for improved targeting of drug therapies to cardiomyocytes.

• Overexpression of catalase in myeloid cells causes impaired postischemic neovascularization.

  Authors: Roberto Hodara, Daiana Weiss, Giji Joseph, Juan C Velasquez-Castano, Natalia Landázuri, Ji Woong Han, Young-sup Yoon, W Robert Taylor

  Arteriosclerosis, thrombosis, and vascular biology. 07/2011; 31(10):2203-9.

  Myeloid lineage cells (MLCs) such as macrophages are known to play a key role in postischemic neovascularization. However, the role of MLC-derived reactive oxygen species in this process and theirMyeloid lineage cells (MLCs) such as macrophages are known to play a key role in postischemic neovascularization. However, the role of MLC-derived reactive oxygen species in this process and their specific chemical identity remain unknown. Transgenic mice with MLC-specific overexpression of catalase (Tg(Cat-MLC) mice) were created on a C57BL/6 background. Macrophage catalase activity was increased 3.4-fold compared with wild-type mice. After femoral artery ligation, laser Doppler perfusion imaging revealed impaired perfusion recovery in Tg(Cat-MLC) mice. This was associated with fewer collateral vessels, as assessed by microcomputed tomography angiography, and decreased capillary density. Impaired functional recovery of the ischemic limb was also evidenced by a 50% reduction in spontaneous running activity. The deficient neovascularization was associated with a blunted inflammatory response, characterized by decreased macrophage infiltration of ischemic tissues, and lower mRNA levels of inflammatory markers, such as tumor necrosis factor-α, osteopontin, and matrix mettaloproteinase-9. In vitro macrophage migration was impaired in Tg(Cat-MLC) mice, suggesting a role for H(2)O(2) in regulating the ability of macrophages to infiltrate ischemic tissues. MLC-derived H(2)O(2) plays a key role in promoting neovascularization in response to ischemia and is a necessary factor for the development of ischemia-induced inflammation.

• Catalase overexpression in aortic smooth muscle prevents pathological mechanical changes underlying abdominal aortic aneurysm formation.

  Authors: Kathryn Maiellaro-Rafferty, Daiana Weiss, Giji Joseph, William Wan, Rudolph L Gleason, W Robert Taylor

  American journal of physiology. Heart and circulatory physiology. 05/2011; 301(2):H355-62.

  The causality of the associations between cellular and mechanical mechanisms of abdominal aortic aneurysm (AAA) formation has not been completely defined. Because reactive oxygen species areThe causality of the associations between cellular and mechanical mechanisms of abdominal aortic aneurysm (AAA) formation has not been completely defined. Because reactive oxygen species are established mediators of AAA growth and remodeling, our objective was to investigate oxidative stress-induced alterations in aortic biomechanics and microstructure during subclinical AAA development. We investigated the mechanisms of AAA in an angiotensin II (ANG II) infusion model of AAA in apolipoprotein E-deficient (apoE(-/-)) mice that overexpress catalase in vascular smooth muscle cells (apoE(-/-)xTg(SMC-Cat)). At baseline, aortas from apoE(-/-)xTg(SMC-Cat) exhibited increased stiffness and the microstructure was characterized by 50% more collagen content and less elastin fragmentation. ANG II treatment for 7 days in apoE(-/-) mice altered the transmural distribution of suprarenal aortic circumferential strain (quantified by opening angle, which increased from 130 ± 1° at baseline to 198 ± 8° after 7 days of ANG II treatment) without obvious changes in the aortic microstructure. No differences in aortic mechanical behavior or suprarenal opening angle were observed in apoE(-/-)xTg(SMC-Cat) after 7 days of ANG II treatment. These data suggest that at the earliest stages of AAA development H(2)O(2) is functionally important and is involved in the control of local variations in remodeling across the vessel wall. They further suggest that reduced elastin integrity at baseline may predispose the abdominal aorta to aneurysmal mechanical remodeling.

• Effect of poly(ethylene glycol) diacrylate concentration on network properties and in vivo response of poly(β-amino ester) networks.

  Authors: David L Safranski, Daiana Weiss, J Brian Clark, Birgitta S Caspersen, W Robert Taylor, Ken Gall

  Journal of biomedical materials research. Part A. 02/2011; 96(2):320-9.

  Poly(β-amino ester) networks have shown promise as tissue scaffolds. The objective of this work was to examine the effect of changing poly(ethylene glycol) diacrylate concentration on poly(β-aminoPoly(β-amino ester) networks have shown promise as tissue scaffolds. The objective of this work was to examine the effect of changing poly(ethylene glycol) diacrylate concentration on poly(β-amino ester) network properties and to assess the degradable polymers' in vivo response, using magnetic resonance imaging (MRI) and immunohistochemistry. The networks were synthesized from hexanediol diacrylate (HDDA), poly(ethylene glycol) diacrylate (PEGDA), and a primary amine, 3-methoxypropylamine (3-MOPA), with a fixed overall molar ratio of diacrylate to amine. Network properties were verified to insure that the networks possessed equivalent initial properties and structure other than chemistry. The effect of varying PEGDA concentration on water content, mass loss, and modulus was determined, where increasing the concentration of PEGDA increases both water content, mass loss rate, and decreases modulus. We also show that manipulating the network composition at ratios of 0:100, 10:90 and 25:75 (PEGDA:HDDA) does not elicit a major inflammatory response to subcutaneous implantation of the networks in mice. This work provides a foundation for tailoring poly(β-amino ester) networks, based on degradation rate and modulus, as a means to tune the polymer properties for various biomedical applications.

• Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves--association with low BMP antagonists and SMAD6.

  Authors: Randall F Ankeny, Vinod H Thourani, Daiana Weiss, J David Vega, W Robert Taylor, Robert M Nerem, Hanjoong Jo

  PloS one. 01/2011; 6(6):e20969.

  Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation ofAortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification. Human calcified AVs obtained from AV replacement surgeries and non-calcified AVs from heart transplantations were used for immunohistochemical studies. We found SMAD-1/5/8 phosphorylation (a canonical BMP pathway) was higher in the calcified fibrosa than the non-calcified fibrosa while SMAD-2/3 phosphorylation (a canonical TGFβ pathway) did not show any difference. Interestingly, we found that BMP-2/4/6 expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both calcified and non-calcified AV cusps; however, BMP antagonists (crossvienless-2/BMPER and noggin) expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both disease states. Moreover, significant expression of inhibitory SMAD-6 expression was found only in the non-calcified ventricularis endothelium. SMAD-1/5/8 is preferentially activated in the calcified fibrosa endothelium of human AVs and it correlates with low expression of BMP antagonists and inhibitory SMAD6. These results suggest a dominant role of BMP antagonists in the side-dependent calcification of human AVs.

• Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension.

  Authors: Antony Vinh, Wei Chen, Yelena Blinder, Daiana Weiss, W Robert Taylor, Jörg J Goronzy, Cornelia M Weyand, David G Harrison, Tomasz J Guzik

  Circulation. 12/2010; 122(24):2529-37.

  The pathogenesis of hypertension remains poorly understood, and treatment is often unsuccessful. Recent evidence suggests that the adaptive immune response plays an important role in this disease.The pathogenesis of hypertension remains poorly understood, and treatment is often unsuccessful. Recent evidence suggests that the adaptive immune response plays an important role in this disease. Various hypertensive stimuli cause T-cell activation and infiltration into target organs such as the vessel and the kidney, which promotes vascular dysfunction and blood pressure elevation. Classically, T-cell activation requires T-cell receptor ligation and costimulation. The latter often involves interaction between B7 ligands (CD80 and CD86) on antigen-presenting cells with the T-cell coreceptor CD28. This study was therefore performed to examine the role of this pathway in hypertension. Angiotensin II-induced hypertension increased the presence of activated (CD86(+)) dendritic cells in secondary lymphatic tissues. Blockade of B7-dependent costimulation with CTLA4-Ig reduced both angiotensin II- and deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Activation of circulating T cells, T-cell cytokine production, and vascular T-cell accumulation caused by these hypertensive stimuli were abrogated by CTLA4-Ig. Furthermore, in mice lacking B7 ligands, angiotensin II caused minimal blood pressure elevation and vascular inflammation, and these effects were restored by transplantation with wild-type bone marrow. T-cell costimulation via B7 ligands is essential for development of experimental hypertension, and inhibition of this process could have therapeutic benefit in the treatment of this disease.

• An in vivo murine model of low-magnitude oscillatory wall shear stress to address the molecular mechanisms of mechanotransduction--brief report.

  Authors: Nick J Willett, Robert C Long, Kathryn Maiellaro-Rafferty, Roy L Sutliff, Richard Shafer, John N Oshinski, Don P Giddens, Robert E Guldberg, W Robert Taylor

  Arteriosclerosis, thrombosis, and vascular biology. 11/2010; 30(11):2099-102.

  Current understanding of shear-sensitive signaling pathways has primarily been studied in vitro largely because of a lack of adequate in vivo models. Our objective was to develop a simple andCurrent understanding of shear-sensitive signaling pathways has primarily been studied in vitro largely because of a lack of adequate in vivo models. Our objective was to develop a simple and well-characterized murine aortic coarctation model to acutely alter the hemodynamic environment in vivo and test the hypothesis that endothelial inflammatory protein expression is acutely upregulated in vivo by low-magnitude oscillatory wall shear stress (WSS). Our model uses the shape memory response of nitinol clips to reproducibly induce an aortic coarctation and allow subsequent focal control over WSS in the aorta. We modeled the corresponding hemodynamic environment using computational fluid dynamics and showed that the coarctation produces low-magnitude oscillatory WSS distal to the clip. To assess the biological significance of this model, we correlated WSS to inflammatory protein expression and fatty streak formation. Vascular cell adhesion molecule-1 expression and fatty streak formation were both found to increase significantly in regions corresponding to acutely induced low-magnitude oscillatory WSS. We have developed a novel aortic coarctation model that will be a useful tool for analyzing the in vivo molecular mechanisms of mechanotransduction in various murine models.

• Temporal effects of catalase overexpression on healing after myocardial infarction.

  Authors: Karl D Pendergrass, Susan T Varghese, Kathryn Maiellaro-Rafferty, Milton E Brown, W Robert Taylor, Michael E Davis

  Circulation. Heart failure. 10/2010; 4(1):98-106.

  Reactive oxygen species, such as hydrogen peroxide (H(2)O(2)), contribute to progression of dysfunction after myocardial infarction (MI). However, chronic overexpression studies do not agree withReactive oxygen species, such as hydrogen peroxide (H(2)O(2)), contribute to progression of dysfunction after myocardial infarction (MI). However, chronic overexpression studies do not agree with acute protein delivery studies. The purpose of the present study was to assess the temporal role of cardiomyocyte-derived H(2)O(2) scavenging on cardiac function after infarction using an inducible system. We developed a tamoxifen-inducible, cardiomyocyte-specific, catalase-overexpressing mouse. Catalase overexpression was induced either 5 days before or after MI. Mice exhibited a 3-fold increase in cardiac catalase activity that was associated with a significant decrease in H(2)O(2) levels at both 7 and 21 days. However, cardiac function improved only at the later time point. Proinflammatory and fibrotic genes were acutely upregulated after MI, but catalase overexpression abolished the increase despite no acute change in function. This led to reduced overall scar formation, with lower levels of Collagen 1A and increased contractile Collagen 3A expression at 21 days. In contrast to prior studies, there were no acute functional improvements with physiological catalase overexpression before MI. Scavenging of H(2)O(2), however, reduced proinflammatory cytokines and altered cardiac collagen isoforms, associated with an improvement in cardiac function after 21 days. Our results suggest that sustained H(2)O(2) levels rather than acute levels immediately after MI may be critical in directing remodeling and cardiac function at later time points.

• A significant improvement of the efficacy of radical oxidant probes by the kinetic isotope effect.

  Authors: Kousik Kundu, Sarah F Knight, Seungjun Lee, W Robert Taylor, Niren Murthy

  Angewandte Chemie (International ed. in English). 08/2010; 49(35):6134-8.

• Shear stress and plaque development.

  Authors: Saurabh S Dhawan, Ravi P Avati Nanjundappa, Jonathan R Branch, W Robert Taylor, Arshed A Quyyumi, Hanjoong Jo, Michael C McDaniel, Jin Suo, Don Giddens, Habib Samady

  Expert review of cardiovascular therapy. 04/2010; 8(4):545-56.

  Although traditional cardiovascular risk factors 'prime the soil' for atherogenesis systemically, atherosclerosis primarily occurs in a site-specific manner with a predilection towards the inner wallAlthough traditional cardiovascular risk factors 'prime the soil' for atherogenesis systemically, atherosclerosis primarily occurs in a site-specific manner with a predilection towards the inner wall of curvatures and outer wall of bifurcations with sparing of flow-dividers. Wall shear stress is a frictional force exerted parallel to the vessel wall that leads to alteration of the endothelial phenotype, endothelial cell signaling, gene and protein expression leading to a proinflammatory phenotype, reduced nitric oxide availability and disruption of the extracellular matrix, which in turn leads to plaque development. Clinical and experimental data are emerging that suggest the pathobiology associated with abnormal wall shear stress results in atherosclerotic plaque development and progression.

• Sustained VEGF delivery via PLGA nanoparticles promotes vascular growth.

  Authors: Justin S Golub, Young-tae Kim, Craig L Duvall, Ravi V Bellamkonda, Divya Gupta, Angela S Lin, Daiana Weiss, W Robert Taylor, Robert E Guldberg

  American journal of physiology. Heart and circulatory physiology. 03/2010; 298(6):H1959-65.

  Technologies to increase tissue vascularity are critically important to the fields of tissue engineering and cardiovascular medicine. Currently, limited technologies exist to encourage angiogenesisTechnologies to increase tissue vascularity are critically important to the fields of tissue engineering and cardiovascular medicine. Currently, limited technologies exist to encourage angiogenesis and arteriogenesis in a controlled manner. In the present study, we describe an injectable controlled release system consisting of VEGF encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). The majority of VEGF was released gradually over 2-4 days from the NPs as determined by an ELISA release kinetics experiment. An in vitro aortic ring bioassay was used to verify the bioactivity of VEGF-NPs compared with empty NPs and no treatment. A mouse femoral artery ischemia model was then used to measure revascularization in VEGF-NP-treated limbs compared with limbs treated with naked VEGF and saline. 129/Sv mice were anesthetized with isoflurane, and a region of the common femoral artery and vein was ligated and excised. Mice were then injected with VEGF-NPs, naked VEGF, or saline. After 4 days, three-dimensional microcomputed tomography angiography was used to quantify vessel growth and morphology. Mice that received VEGF-NP treatment showed a significant increase in total vessel volume and vessel connectivity compared with 5 microg VEGF, 2.5 microg VEGF, and saline treatment (all P < 0.001). When the yield of the fabrication process was taken into account, VEGF-NPs were over an order of magnitude more potent than naked VEGF in increasing blood vessel volume. Differences between the VEGF-NP group and all other groups were even greater when only small-sized vessels under 300 mum diameter were analyzed. In conclusion, sustained VEGF delivery via PLGA NPs shows promise for encouraging blood vessel growth in tissue engineering and cardiovascular medicine applications.

• Bioartificial matrices for therapeutic vascularization.

  Authors: Edward A Phelps, Natalia Landázuri, Peter M Thulé, W Robert Taylor, Andrés J García

  Proceedings of the National Academy of Sciences of the United States of America. 02/2010; 107(8):3323-8.

  Therapeutic vascularization remains a significant challenge in regenerative medicine applications. Whether the goal is to induce vascular growth in ischemic tissue or scale up tissue-engineeredTherapeutic vascularization remains a significant challenge in regenerative medicine applications. Whether the goal is to induce vascular growth in ischemic tissue or scale up tissue-engineered constructs, the ability to induce the growth of patent, stable vasculature is a critical obstacle. We engineered polyethylene glycol-based bioartificial hydrogel matrices presenting protease-degradable sites, cell-adhesion motifs, and growth factors to induce the growth of vasculature in vivo. Compared to injection of soluble VEGF, these matrices delivered sustained in vivo levels of VEGF over 2 weeks as the matrix degraded. When implanted subcutaneously in rats, degradable constructs containing VEGF and arginine-glycine-aspartic acid tripeptide induced a significant number of vessels to grow into the implant at 2 weeks with increasing vessel density at 4 weeks. The mechanism of enhanced vascularization is likely cell-demanded release of VEGF, as the hydrogels may degrade substantially within 2 weeks. In a mouse model of hind-limb ischemia, delivery of these matrices resulted in significantly increased rate of reperfusion. These results support the application of engineered bioartificial matrices to promote vascularization for directed regenerative therapies.

• Vascular wall ACE is not required for atherogenesis in ApoE(-/-) mice.

  Authors: Daiana Weiss, Kenneth E Bernstein, Sebastian Fuchs, Jonathan Adams, Andreas Synetos, W Robert Taylor

  Atherosclerosis. 10/2009;

  BACKGROUND: It has been proposed that elements of the renin angiotensin system expressed in the arterial wall are critical for the development of atherosclerosis. Angiotensin converting enzyme (ACE)BACKGROUND: It has been proposed that elements of the renin angiotensin system expressed in the arterial wall are critical for the development of atherosclerosis. Angiotensin converting enzyme (ACE) is highly expressed by the endothelium and is responsible for a critical enzymatic step in the generation of angiotensin II. However, the functional contribution of ACE expression in the vascular wall in atherogenesis is unknown. Therefore, we made use of unique genetic models in which mice without the expression of ACE in the vascular wall were crossed with ApoE(-/-) mice in order to determine the contribution of tissue ACE expression to atherosclerotic lesion formation. METHODS AND RESULTS: Mice expressing either a soluble form of ACE (ACE 2/2) or mice with somatic ACE expression restricted to the liver and kidney (ACE 3/3) on an ApoE(-/-) background were placed on a standard chow or Western diet for 6 months. Atherosclerotic lesion area in the ACE 2/2 mice was significantly lower than that seen in the ACE 3/3 mice. However, these animals also had significantly lower blood pressure and reduced plasma ACE activity which precluded establishing a specific causal relationship between absent tissue ACE activity and decreased atherosclerotic lesion extent. Therefore, we studied the ACE 3/3 mice which are normotensive and lack vascular ACE expression. In the ACE 3/3 animals, atherosclerotic lesion area was not different from wild type controls despite reduced plasma ACE activity. CONCLUSIONS: We concluded that under these experimental conditions, expression of ACE in the arterial wall is not required for atherosclerotic lesion formation.