With each heartbeat, major arteries experience circumferential expansion due to internal pressure changes. This pulsatile force is called cyclic strain and has been implicated in playing a pivotal role in the genetic regulation of vascular physiology and pathology. This dissertation investigates the hypothesis that in human umbilical vein endothelial cells (HUVEC), pathological levels of cyclic strain activate the c-Myc promoter, leading to c-Myc transcription and downstream gene induction. To determine expression and time-dependency of c-Myc in HUVEC, mRNA and protein expression of c-Myc under physiological (6-10% cyclic strain) and pathological conditions (20% cyclic strain) were studied. Both c-Myc mRNA and protein expression increased more than three-fold in HUVEC (P4-P5) cyclically-strained at 20%. This expression occurred in a time-dependent manner, peaking in the 1.5-2 hour range and falling to basal levels by 3 hours. Subsequently, the mechanism of c-Myc transcription was investigated by using specific inhibitors to modulate c-Myc transcriptional activation. These compounds, obtained from the University of Arizona Cancer Center, attenuated cyclic-strain-induced c-Myc transcription by about 50%. Having established this reduction in expression, it was investigated how these effects modulate downstream genes that are regulated by c-Myc. The results indicate that direct targeting of the c-Myc promoter may decrease stretch-induced gene expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA) and heat shock protein 60 (HSP60). These findings may help in the development of a novel therapeutic opportunity in vascular diseases.

The failure behavior of collagenous soft tissues is important for clinical problems of plaque rupture and trauma. Cyclic tests require high frequencies that may affect the strength properties of the soft tissues. Experimental results of mechanical response of blood vessels to physiologic loads can be used to model and predict plaque rupture and direct medical therapy or surgical intervention. The goal of the study is to measure the mechanical failure properties of arteries to determine if they are strain rate and cycle dependant and to measure the progressive damage of arteries with time dependent loading. Ring specimens of porcine carotid arteries were preconditioned and then pulled to failure. In all cases, the intima broke first. Ultimate stress increased as a weak function of increasing strain rates. The ultimate stress at 100 mm/s was 4.54 MPa, greater than the 3.26 MPa at 0.1 mm/s. Strain rates between 1 and 100 mm/s correspond to a cyclic frequency of 0.5 Hz to 5 Hz for fatigue testing. In contrast, ultimate strain in arteries was independent of strain rate over the range tested. The creep tests showed a logarithmic relationship between stress magnitude and stress duration for this soft tissue. The creep testing indicates that damage is accumulating above certain threshold stress levels. The values of ultimate strength showed a 35% increase after 10,000 cycling loading. In contrast, the ultimate strain had a 13% decrease after cycling and the difference was statistically significant with p=0.018. The testing results showed that there were no significant differences on strength among fresh arteries and arteries stored at 5¡ã C for up to two weeks. The test results may be useful for developing a mathematical model to predict the behavior of arterial soft tissues and may be extended to estimate fracture and fatigue in the atherosclerotic plaque cap.

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The engineering of human vascular grafts is an intense area of study since there is crucial need for alternatives to native vein or artery for vascular surgery. This current study sought to prove that a tissue engineered blood vessel (TEBV) 1mm in diameter could be developed from human smooth muscle cells and that endothelial progenitor cells (EPCs) could be cultured and used to endothelialize these grafts. This project had four specific aims: the isolation and characterization of EPCs, the seeding of a novel scaffold with EPCs and exposure to physiologic shear stress in vitro, the development of TEBV from human smooth muscle cells that are strong enough to implant in vivo, and the in vivo implantation of TEBV into the rat aortic model with a comparison of EPC seeded TEBVs pretreated with shear stress and unseeded TEBVs. The results yielded isolation of four EPC lines and a flow system design capable of seeding EPCs onto a novel scaffold with preliminary studies indicating that it is capable of exposing the EPCs to physiologic shear stress, although further studies require more optimization. The development of mechanically strong TEBV was highly successful, yielding TEBVs comparable to native vessels in collagen density and burst pressure, but with much lower compliance. Current implantation studies indicated that unseeded TEBV grafts implanted into the rat aorta without anticoagulation is highly thrombogenic. However, anticoagulation using Plavix may be capable of maintaining graft patency. These TEBVs did not rupture or form aneurysm in vivo and the future completion of the in vivo studies are likely to demonstrate the high potential of these grafts.

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Master / Master of Research in Medicine

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy

Physical load, age and gender influence to blood pressure and maximal stresses in the pathological blood vessel palaces was studies in this work. The main research subject – pathological blood vessel and its blood flow processes that depend on physical load, pathology degree and type, age, gender and blood vessels stress characteristics. The main aim of this work – to examine blood flow characteristics, local blood pressure, stress distribution in the pathological blood vessels dependent physical load assessing blood vessels mechanical properties variations due to age, gender, blood vessel pathology type; to make simplified human efficiency evaluation methodology. The paper analyse a few main tasks: to explore physical load, blood vessels pathology degree, age and gender influence to blood pressure and tensions increase in the pathological blood vessels locations; experimentally determine blood flow rates changes in pathological blood vessels assessing; additionally investigate blood pressure and heart rate characteristics variations during set physical load and human working age range. This paper consists of introduction, four chapters, summary, literature and authors publications theses lists and two annexes. Introductory chapter discusses the test problem, work topicality, research subject, also formulates work subject and tasks, and describes research methodology, work scientific novelty, practical value of the work results, defended propositions. In the introduction end... [to full text] / Disertacijoje nagrinėjama fizinio krūvio, amžiaus bei lyties įtaka kraujo spaudimui ir didžiausiems įtempiams pažeistoje kraujagyslės vietoje. Pagrindinis tyrimo objektas – ligos pažeista kraujagyslė ir joje vykstantys kraujo tėkmės procesai, priklausantys nuo fizinio krūvio dydžio, pažeidimo laipsnio ir rūšies, amžiaus, lyties, bei šių veiksnių įtaka didžiausiems įtempiams ir spaudimui pažeistose vietose. Pagrindinis disertacijos tikslas – ištirti kraujo tėkmės charakteristikas, lokalinį kraujo spaudimą, įtempių pasiskirstymą pažeistose kraujagyslėse priklausomai nuo fizinio krūvio, įvertinant kraujagyslių mechaninių savybių pokytį dėl amžiaus, lyties, kraujagyslės pažeidimo rūšies, ir sudaryti supaprastintą darbingumo verti-nimo metodiką. Darbe sprendžiami keli uždaviniai: ištirti fizinės apkrovos dydžio, kraujagyslių pažeidimų laipsnio, amžiaus ir lyties įtaką kraujo spaudimui ir įtempių padidėjimui pažeistose kraujagyslių vietose; ekspe-rimentiniu būdu nustatyti kraujo tėkmės rodiklių pokyčius pažeistose kraujagyslėse; ištirti kraujo spaudimo ir širdies susitraukimų dažnio charakteristikų pokyčius nustatytame fizinio krūvio ir žmogaus darbingo amžiaus intervale. Disertaciją sudaro įvadas, keturi skyriai, rezultatų apibendrinimas, naudotos literatūros ir autorės publikacijų disertacijos tema sąrašai ir du priedai. Įvadiniame skyriuje aptariama tiriamoji problema, darbo aktualumas, aprašomas tyrimų objektas, formuluojamas darbo tikslas bei uždaviniai, aprašoma tyrimų... [toliau žr. visą tekstą]

Methylenetetrahydrofolate reductase catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for the remethylation of homocysteine to methionine. Patients with severe MTHFR deficiency have $<$20% residual enzyme activity, moderate hyperhomocysteinemia, vascular lesions and neurological dysfunction. Mildly-deficient individuals with a thermolabile enzyme are at increased risk for developing cardiovascular disease. / Two MTHFR sequence changes were identified. The first was a C to T transition at bp 764 altering a proline to a leucine codon; this change was found in one severely-deficient patient. The second was a C to T transition at bp 677, substituting a valine for a highly-conserved alanine codon. The $ rm A to V$ substitution was identified on 35-40% of chromosomes. Expression of the $ rm A to V$ mutation in prokaryotic cells revealed increased thermolability over the wild-type enzyme. Genotyping for the $ rm A to V$ mutation in three vascular disease studies showed that it was associated with mild hyperhomocysteinemia, a risk factor for vascular disease. / The preventative effects of folate supplementation on the occurrence and recurrence of neural tube defects (NTDs) have been repeatedly demonstrated. The curly-tail (ct) mouse model for NTDs was used to investigate the involvement of MTHFR in these defects. Ct mice had significantly increased homocysteine levels although differences in MTHFR activity were not demonstrated. The mouse MTHFR gene was mapped to distal chromosome 4, close to the major gene for NTDs in ct. MTHFR is suggested as a candidate locus for the ct defect.