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Gene Expression Profile Signatures Indicate a Role for Wnt Signaling in Endothelial Commitment From Embryonic Stem Cells
- Hong Wang,
- Peter C. Charles,
- Yaxu Wu,
- Rongqin Ren,
- Xinchun Pi,
- Martin Moser,
- Michal Barshishat-Kupper,
- Jeffrey S. Rubin,
- Charles Perou,
- Victoria Bautch and
- Cam Patterson
Circulation Research Volume 98, Issue 1026 May 2006

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We have used global gene expression analysis to establish a comprehensive list of candidate genes in the developing vasculature during embryonic (ES) cell differentiation in vitro. A large set of genes, including growth factors, cell surface molecules, transcriptional factors, and members of several signal transduction pathways that are known to be involved in vasculogenesis or angiogenesis, were found to have expression patterns as expected. Some unknown or functionally uncharacterized genes were differentially regulated in flk1⁺ cells compared with flk1⁻ cells, suggesting possible roles for these genes in vascular commitment. Particularly, multiple components of the Wnt signaling pathway were differentially regulated in flk1⁺ cells, including Wnt proteins, their receptors, downstream transcriptional factors, and other components belonging to this pathway. Activation of the Wnt signal was able to expand vascular progenitor populations whereas suppression of Wnt activity reduced flk1⁺ populations. Suppression of Wnt signaling also inhibited the formation of matured vascular capillary-like structures during late stages of embryoid body differentiation. These data indicate a requisite and ongoing role for Wnt activity during vascular development, and the gene expression profiles identify candidate components of this pathway that participate in vascular cell differentiation.
Abstract P2036: Investigating Variants Of Hdac7In Mammalian Heart Regeneration
- Tyler Buddell,
- Alexandra Purdy,
- Xiangwen Peng,
- Mary Kolell,
- Samantha Swift,
- Samantha Paddock,
- Caitlin Omeara and
- Michaela Patterson
Circulation Research Volume 131, Issue Suppl_15 August 2022

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The longstanding belief in the field is the mammalian heart is incapable of regenerating. However, findings regarding the variability of regenerative capacity of mammalian hearts are opening the door for such a possibility. Mononuclear diploid cardiomyocytes (MNDCMs) are a subpopulation of CMs believed to be capable of mounting a regenerative response and the prevalence of the MNDCM population in mammalian hearts is a variable trait. Thus, if we can understand the genetic mechanisms governing the MNDCM variability, it could indicate strategies to stimulate an endogenous regenerative response. Using a genome-wide association approach across a panel of genetically diverse inbred mice, Dr. Patterson identified genes associated with the frequency of MNDCMs in the uninjured adult heart. From this genetic screen, she validated the gene Tnni3k as one regulator of CM ploidy and regenerative competence after injury. Here, we follow a second novel locus identified from this screen found on chromosome 15, which includes the gene Hdac7. Previously published RNA-seq data on isolated CMs indicate that Hdac7 expression levels increase during the first postnatal week, a time that coincides with the onset of cellular senescence, CM polyploidization, and the loss of innate regenerative capacity in the heart. Using a CM specific Hdac7 conditional knockout mouse, we found that loss of Hdac7 in CMs from birth increases CM DNA synthesis, increases CM ploidy, and increases average CM cell length. Moreover, we identified a protein coding variant of Hdac7 that corresponds to differences in frequency of MNDCM between members of the mouse diversity panel. Finally, we have gathered preliminary findings that suggest genetic epistasis between Hdac7 and Tnni3k. Specifically, Hdac7;Tnni3k double knockout animals display more MNDCMs than Tnni3k knockout did on its own. Our findings suggest Hdac7 negatively regulates DNA synthesis; a key part of the cell cycle that has the potential as a therapeutic target for the stimulation of a proliferation response. In addition, these findings showcase complex genetic interactions regulating CM regeneration, suggesting that combinatorial approaches can enhance regenerative responses.
Single Plane Vs Biplane Studies In Coronary Artery Disease
- JOHN H. K. VOGEL
Circulation Volume 48, Issue 31 September 1973

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The Effect of Moderate Changes in Blood Volume on Left and Right Atrial Pressures
- JAMES P. HENRY,
- OTTO H. GAUER and
- HERBERT O. SIEKER
Circulation Research Volume 4, Issue 11 January 1956

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The blood volume of 15 dogs was progressively increased an estimated 30 per cent by repeated blood infusions and decreased 30 per cent by stepwise hemorrhage. The pressures in the venous system, both atria and the pulmonary artery, rose and fell in unison with these moderate changes in blood volume and the new levels remained stable for at least 10 to 20 minutes.Although the right ventricle anatomically separates the systemic venous bed from the pulmonary circulation, small hemorrhages and transfusions have so little effect on its activity that, from the point of view of pressure volume relationships, the systemic veins and the left atrium are parts of the same functional unit.
Changes in Central Venous Pressure after Moderate Hemorrhage and Transfusion in Man
- OTTO H. GAUER,
- JAMES P. HENRY and
- HERBERT O. SIEKER
Circulation Research Volume 4, Issue 11 January 1956

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Changes in central venous pressure were recorded continuously before, during and for 40 to 50 minutes after hemorrhage and transfusion in the amounts of 6.5 cc. per Kg. and 8.1 cc. per Kg. The pressures obtained 15 to 20 minutes after onset of blood volume changes were independent of the rate of hemorrhage or transfusion. In the average subject of 70 Kg., ΔP/ΔV for zero time was 0.7 cm. of water pressure change per 100 cc. volume change. Recovery from hemorrhage was imperceptible during the one hour observation period, but recovery from transfusion was slightly faster.
Abstract 1990: Calcium Channel Blockers Impair Right Atrial Contractility and Cardiac Output in Non-Responders with Chronic Pulmonary Hypertension
- Andreas Zierer,
- Sydney L Gaynor,
- Hersh S Maniar,
- Paul Steendijk,
- Alexander G Patterson and
- Marc R Moon
Circulation Volume 114, Issue suppl_1831 October 2006

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Background. The use of Calcium Channel Blockers (CCB) in patients with chronic pulmonary hypertension (CPH) is controversial. Concern exists that CCB therapy in “non-responders” may further impair cardiac function, but their effects on right heart mechanics in “responders” versus non-responders remains unknown.Methods. In 12 dogs, right atrial (RA) and ventricular (RV) pressure and volume (conductance catheter) were simultaneously recorded after 3 months of progressive pulmonary artery banding (baseline). Diltiazem was given at 10 mg/h with the pulmonary artery constricted (CCB non-responder). Responders were then simulated by releasing the pulmonary artery band to unload the ventricle. RA and RV contractility and diastolic stiffness (slope of end-systolic and end-diastolic pressure-volume relations) were calculated and RA reservoir and conduit function were quantified as RA inflow with the tricuspid valve closed versus open, respectively.Results. With CCB, RA contractility (p < 0.03) and cardiac output (p < 0.004) decreased in non-responders while RV pressure and contractility were unchanged (table). After pulmonary artery band release, the right atrium became less distensible, causing a shift from reservoir to conduit function (p < 0.001) and the contractility in both chambers decreased (p < 0.007). RA and RV diastolic function in non-responders and responders was not affected by CCB.Conclusions. CCB did not impact RV function in non-responders, but significantly impaired RA contractility and cardiac output. In responders, afterload fell substantially to maintain cardiac output despite a decline in the normal RA and RV hyperdynamic contractile response to CPH. Thus, clinical use of CCB in CPH should be restricted to documented responders.Effects of CCB in non-responders versus responders with chronic pulmonary hypertension (baseline).
Distribution of Blood Flow in the Digestive Tract of the Rat
- SHELDON H. STEINER and
- GUSTAVE C. E. MUELLER
Circulation Research Volume 9, Issue 11 January 1961

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The rubidium fractionation technique has been used to make comparative measurements of functional perfusion rates in the gastrointestinal tract of relatively undisturbed but fasted and anesthetized rats. The duodenum has the highest functional perfusion rate per unit mass of the entire digestive tract; the stomach is less than half as well perfused. The remainder of the tract to the rectosigmoid shows a progressive decrease. The small intestine shows a progressive increase in functional flow per unit mass from the pylorus to the ligament of Treitz and then a progressive decrease, most marked in the jejunum to the ileocecal valve. Blood flow values to other structures of the gastrointestinal tract are also given.
The Continuous Recording of Central Venous Pressure Changes from an Arm Vein
- OTTO H. GAUER and
- HERBERT O. SIEKER
Circulation Research Volume 4, Issue 11 January 1956

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With the subject in the right lateral decubitus position, changes of central venous pressure can be recorded accurately and conveniently from a vein in the antecubital fossa of the dependent arm. Theoretically the hydrostatic, pressure transforms the venous bed between the heart and the site of puncture into uninterrupted wide channels with relatively low distensibility. Simultaneous recordings of pressure by the method described and by catheterization of the central veins showed that induced changes of central venous pressure were identically recorded from both sites. The mean pressure gradient between the peripheral and central veins was 35 mm. of water.
Hemodynamic Effects of Hypovolemia in Normal Subjects and Patients with Congestive Heart Failure
- R. H. MURRAY,
- L. J. THOMPSON,
- J. A. BOWERS,
- E. F. STEINMETZ and
- C. D. ALBRIGHT
Circulation Volume 39, Issue 11 January 1969

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Five young normal subjects (NS) and six middle-aged patients with chronic, low-output, congestive heart failure (HFP) were studied before and after 10 minutes of exposure to hypovolemia induced by negative pressure (30 mm Hg) applied to the lower body. ECG, respirometer, and catheters placed in the subclavian artery and superior vena cava permitted measurements of heart rate (HR), respiration rate, arterial and central venous pressures (CVP), and cardiac output (CO). In the group of NS, systemic vascular resistance (SVR) rose moderately, while CVP fell 4.3 mm Hg; CO, stroke volume (SV), stroke work (SW), and central blood volume (CBV) fell about 20%, whereas blood pressure and HR showed little change. In the group of HFP, control hemodynamic values were generally abnormal. In four patients the response to hypovolemia was similar to that of NS. Two patients with advanced heart failure showed no change or a rise in CO, SV, and SW in the face of a fall in CVP (3.1 and 3.7 mm Hg), no change or a fall in SVR, and a rise in CBV. It is concluded that HFP does not respond to hypovolemia in a consistent manner. Certain patients with advanced failure demonstrated abnormal responses to induced hypovolemia, the causes for which are complex.
Epidemiologic and Genetic Studies of Congenital Heart Disease in the Dog
- D. F. PATTERSON
Circulation Research Volume 23, Issue 21 August 1968

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The prevalence rate for cardiovascular malformations in dogs presented to a large university veterinary clinic was 6.8 per 1000. Patent ductus arteriosus, as in man, was found predominantly in females. Breed-specific prevalence rates were significantly greater in purebred dogs than in mongrels, and the breed distributions of patent ductus arteriosus, pulmonic stenosis, subaortic stenosis, persistent right aortic arch, and tetralogy of Fallot were significantly different than would be expected if all breeds were equally susceptible to each type of malformation. On the basis of these observations, two hypotheses were made: (1) Genetic factors are determinants of certain types of congenital heart disease in the dog. (2) These genetic factors have specific effects on cardiac morphogenesis, resulting in specific types of cardiovascular malformations. Preliminary genetic studies confirmed the specific hereditary transmission of valvular pulmonic stenosis in beagles, persistent right aortic arch in German shepherds, and conal septal defects (including ventricular septal defects and tetralogy of Fallot) in keeshonden. The pattern of inheritance of these defects was not consistent with any simple genetic hypothesis. Patent ductus arteriosus in dogs of poodle ancestry and fibrous subaortic stenosis in Newfoundlands were shown provisionally to be transmitted in a manner consistent with autosomal dominant inheritance. The significance of these findings is considered in relation to present and future understanding of the etiology and pathogenesis of congenital heart disease.
Regulatory T Cells Limit Vascular Endothelial Injury and Prevent Pulmonary Hypertension
- Rasa Tamosiuniene,
- Wen Tian,
- Gundeep Dhillon,
- Lijuan Wang,
- Yon K. Sung,
- Lajos Gera,
- Andrew J. Patterson,
- Rani Agrawal,
- Marlene Rabinovitch,
- Kelly Ambler,
- Carlin S. Long,
- Norbert F. Voelkel and
- Mark R. Nicolls
Circulation Research Volume 109, Issue 830 September 2011

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Rationale:Pulmonary arterial hypertension (PAH) is an incurable disease associated with viral infections and connective tissue diseases. The relationship between inflammation and disease pathogenesis in these disorders remains poorly understood.Objective:To determine whether immune dysregulation due to absent T-cell populations directly contributes to the development of PAH.Methods and Results:Vascular endothelial growth factor receptor 2 (VEGFR2) blockade induced significant pulmonary endothelial apoptosis in T-cell-deficient rats but not in immune-reconstituted (IR) rats. T cell–lymphopenia in association with VEGFR2 blockade resulted in periarteriolar inflammation with macrophages, and B cells even prior to vascular remodeling and elevated pulmonary pressures. IR prevented early inflammation and attenuated PAH development. IR with either CD8 T cells alone or with CD4-depleted spleen cells was ineffective in preventing PAH, whereas CD4-depleting immunocompetent euthymic animals increased PAH susceptibility. IR with either CD4⁺CD25^hi or CD4⁺CD25⁻ T cell subsets prior to vascular injury attenuated the development of PAH. IR limited perivascular inflammation and endothelial apoptosis in rat lungs in association with increased FoxP3⁺, IL-10- and TGF-β-expressing CD4 cells, and upregulation of pulmonary bone morphogenetic protein receptor type 2 (BMPR2)–expressing cells, a receptor that activates endothelial cell survival pathways.Conclusions:PAH may arise when regulatory T-cell (Treg) activity fails to control endothelial injury. These studies suggest that regulatory T cells normally function to limit vascular injury and may protect against the development of PAH.
Apparent improvement in canine collateral myocardial blood flow during vasodilation depends on criteria used to identify ischemic myocardium.
- R E Patterson and
- E S Kirk
Circulation Research Volume 47, Issue 11 July 1980

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Response of Pial Precapillary Vessels to Changes in Arterial Carbon Dioxide Tension
- A. JARRELL RAPER,
- HERMES A. KONTOS and
- JOHN L. PATTERSON
Circulation Research Volume 28, Issue 51 May 1971

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A quantitative study of responses of pial precapillary vessels to changes in arterial blood carbon dioxide tension was made in anesthetized cats. All vessels examined ranging in diameter from 13 to 90μ responded to hypercapnia with increases in diameter and to hypocapnia with decreases in diameter. The onset of the response to hypercapnia was earlier, its speed was faster, and its magnitude greater with higher concentrations of CO₂. In response to the same increase in arterial blood PCO₂, smaller vessels (13 to 40μ) increased in diameter by 47.7 ± 10.8% of the control value while the increase in diameter of larger vessels (41 to 90μ) was significantly lower and equal to 29.5 ± 6.3% of the control value. In the steady state the relation between pial vessel diameter expressed as percent of the control value (Y) and arterial blood PCO₂ (X) was given by the equation Y = 53.07 + 1.587 X – 0.00715 X². The relatively large magnitude of the response of pial arteries and arterioles to CO₂ and the fact that it was dependent on vessel size show that there must be significant readjustments in the pressure gradients in these vessels when CO₂ tension is changed.
Coronary steal mechanisms in dogs with one-vessel occlusion and other arteries normal.
- R E Patterson and
- E S Kirk
Circulation Volume 67, Issue 51 May 1983

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Analysis of vasoactivity of local pH, PCO2 and bicarbonate on pial vessels.
- H A Kontos,
- A J Raper and
- J L Patterson
Stroke Volume 8, Issue 31 May 1977

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The mechanism by which the local effect of CO2ON pial arterioles is exerted was examined in anesthetized cats equipped with a cranial window for the direct observation of the microcirculation of the parietal cortex. The dilation of pial arterioles in response to application of artificial cerebrospinal fluid with low pH was the same whether or not the PCO2 of the solution was maintained in the normal range or markedly increased. The constriction of pial arterioles in response to application of artificial cerebrospinal fluid with high pH was the same whether or not the PCO2 of the solution was maintained in the normal range or markedly decreased. Finally, pial arterioles did not change their caliber in response to application of cerebrospinal fluid with unchanged pH but markedly increased or decreased Pco, or bicarbonate ion concentration. These results show that the action of CO2 on cerebral vessels is exerted via changes in extracellular fluid pH and that molecular CO2 and bicarbonate ions do not have independent vasoactivity on these vessels.
Unresponsiveness of Pial Precapillary Vessels to Catecholamines and Sympathetic Nerve Stimulation
- A. Jarrell Raper,
- Hermes A. Kontos,
- Enoch P. Wei and
- John L. Patterson
Circulation Research Volume 31, Issue 21 August 1972

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A systematic analysis of the possible existence of neurogenic control of precapillary pial vessels was made in three species (cat, dog, and rabbit). In all of these animals, pial vessels failed to respond to externally applied isoproterenol or norepinephrine in high concentrations (up to 100 µg/ml), although the vessels did dilate in response to externally applied histamine. Adrenergic nerve endings on the pial vessels were demonstrated by fluorescent histochemical techniques specific for catecholamines. However, in the absence of changes in arterial blood pressure and arterial blood carbon dioxide tension, pial precapillary vessels showed no change in caliber in response to stimulation of the ipsilateral superior cervical ganglion. These results show that pial precapillary vessels are not subject to vasoconstriction probably because they lack sufficient receptors for the catecholamine neurotransmitter.
Ventricular fibrillation in a conscious canine preparation of sudden coronary death--prevention by short- and long-term amiodarone administration.
- E Patterson,
- B T Eller,
- G D Abrams,
- J Vasiliades and
- B R Lucchesi
Circulation Volume 68, Issue 41 October 1983

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Abstract Number ‐ 181: Anterograde versus Retrograde approaches in the Endovascular Management of Tandem Lesions
- Cynthia B Zevallos,
- Milagros Galecio‐Castillo,
- Mudassir Farooqui,
- Michael Abraham,
- Afshin Divani,
- Marc Ribo,
- Nils Petersen,
- Johanna Fifi,
- Waldo Guerrero,
- Amer Malik,
- James Siegler,
- Thanh N Nguyen,
- Sunil A Sheth,
- Albert J Yoo,
- Guillermo Linares,
- Nazli Janjua,
- Darko Quispe‐Orozco,
- Wondewossen Tekle,
- Marion Oliver,
- Syed Zaidi,
- Alicia Castonguay,
- Jessica Kobsa,
- Ayush Prasad,
- Asad Ikram,
- Hamza Answer,
- Mary Patterson,
- Manuel Requena,
- Marta Olive,
- Abid Qureshi,
- Tiffany Barkley,
- Stavros Matsoukas,
- Ameena Rana,
- Mohamad Abdalkader,
- Sergio Salazar‐Marioni,
- Jazba Soomro,
- Juan Vivanco‐Suarez,
- Aaron Rodriguez‐Calientes,
- Charoskhon Turabova,
- Randall Edgell,
- Maxim Mokin,
- Dileep Yavagal,
- Osama Zaidat,
- Mouhammad Jumaa,
- Ameer Hassan and
- Santiago Ortega‐Gutierrez
Stroke: Vascular and Interventional Neurology Volume 3, Issue S11 March 2023

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IntroductionThere are two approaches for treating stroke patients with tandem occlusions: the anterograde approach (AA, extracranial lesions first) and the retrograde approach (RA, intracranial lesion first). Both techniques are associated with favorable functional outcomes. We aimed to compare both techniques for efficacy and safety outcomes in a multicenter study.MethodsPatient data were pooled from 17 centers and divided into AA and RA groups. We performed multivariable logistic regressions to evaluate the association between each group with efficacy and safety outcomes.Results552 patients were included in the study, 270 (48.4%) were treated with the AA, and 288 (51.6%) with the RA. There were no differences between groups for functional outcome (mRS 0–2) at 90 days (aOR = 0.93, 95%CI: 0.58‐1.48, p = 0.75), and successful reperfusion [mTICI >2b] (aOR = 0.83, 95%CI: 0.44‐1.56, p = 0.57). Similarly, we did not observe any differences for safety outcomes related to sICH (OR = 0.57, 95%CI: 0.25‐1.29, p = 0.18), parenchymal hematoma type 2 (OR = 0.61, 95%CI: 0.3‐1.22, p = 0.16), and all‐cause mortality at 90 days (OR = 1.22, 95%CI: 0.66‐2.26, p = 0.52). However, the median puncture‐to‐reperfusion time was higher in AA compared with RA [59 minutes (IQR: 38–92) vs 53.5 minuntes (IQR: 37–87)].ConclusionsThe AA and RA approaches for the treatment of tandem occlusions seem to achieve similar efficacy and safety outcomes. These results are consistent with those of a previous multi‐center study. Additionally, and in line with previous research, there is a puncture‐to‐reperfusion time difference between both approaches, which suggests a potential benefit when using the RA. However, further prospective randomized studies are needed to elucidate its benefit in achieving better clinical outcomes.
Hereditary Patent Ductus Arteriosus and Its Sequelae in the Dog
- D. F. Patterson,
- R. L. Pyle,
- J. W. Buchanan,
- E. Trautvetter and
- D. A. Abt
Circulation Research Volume 29, Issue 11 July 1971

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Further studies of hereditary patent ductus arteriosus (PDA) in the dog show the defect to have a graded phenotypic expression. A high proportion of offspring of test matings had a fully patent ductus arteriosus, while a smaller proportion had a blind diverticulum of the ductus arteriosus which communicated with the aorta. This is considered to be a forme fruste of PDA, representing incomplete closure. Approximately 50% of pups with fully patent ductus arteriosus developed signs of left heart failure, and about 15% developed severe pulmonary hypertension with right-to-left or bidirectional shunts. Genetic analysis indicated that hereditary PDA in the dog is not a simple mendelian trait, Rather, it resembles a quasi-continuous or threshold trait with a high degree of heritability. Results were analyzed using a polygenic model with two developmental thresholds. Liability to defective closure of the ductus arteriosus increased with the proportion of the genome received from dogs with PDA. Moreover, in pups which had PDA, the incidence of serious sequelae (left heart failure and severe pulmonary hypertension) increased in a parallel fashion, suggesting that an increased liability to PDA was accompanied by an increase in the severity of the lesion.
Evidence for an adenosine receptor on the surface of dog coronary myocytes.
- R A Olsson,
- C J Davis,
- E M Khouri and
- R E Patterson
Circulation Research Volume 39, Issue 11 July 1976

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Adenosine and theophylline were linked covalently to oxidized stachyose to produce compounds too large to penetrate cell membranes. These compounds were used in two conscious and six open-chest anesthetized dogs to test the hypothesis that there is an adenosine receptor on the surface of the coronary myocyte. Intracoronary infusions of the adenosine derivative produced dose-dependent coronary vasodilation which was antagonized by theophylline; two types of theophylline derivative antagonized the coronary vasodilatory action of adenosine. Although these results show that both adenosine and theophylline exert their coronary effects at the surface of the smooth muscle cells, this evidence does not establish that they are competing for a common receptor.

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