Cerebrovascular disease continues to be responsible for significant morbidity and mortality. There is a pressing need to better understand the biomechanics of both intracranial arteries and the extracranial arteries that feed these vessels. Histology and immunohistochemistry were performed on basilar and carotid arteries and elucidated their structural differences. Nonlinear optical microscopy (NLOM) provided collagen fiber orientation and distribution, which offered motivation for a more microstructrually-based model. Biaxial testing was performed on acute basilar and carotid arteries and cultured basilar arteries. We used a validated 2D, four fiber family constitutive relation to model passive biaxial stress-stretch behaviors of basilar and common carotid arteries, and we developed a new relation to model their active biaxial responses. Residual stress information from opening angles and collagen fiber orientation were used to create a 3D fiber distribution constitutive relation. Passive biaxial stress-stretch behavior of basilar arteries was modeled with the 3D fiber distribution constitutive relation and was combined with our new active relation to model the active response of basilar arteries. These data and 2D, four fiber family and active constitutive relation allow the first full comparison of circumferential and axial biomechanical behaviors between a muscular (basilar) and an elastic (carotid) artery from the same species. Our active model describes the responses by both types of vessels to four doses of the vasoconstrictor endothelin-1 (10^-10, 10^-9, 10^-8, 10^-7 M) and predicts levels of smooth muscle activation associated with basal tone under specific in vitro testing conditions. Cultured arteries revealed smooth muscle tone is necessary for vascular remodeling. Our 3D model allowed for the calculation of stress through the wall in passive basilar arteries. These results advance our understanding of the biomechanics of intracranial and extracranial arteries, which is needed to understand better their differential responses to similar perturbations in hemodynamic loading.

Thesis (M. Phil.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 134-145).

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Mechanical Engineering. Title from title-page of electronic thesis. Bibliography: leaves 98-106.

Thesis (Ph.D.)--Indiana University, 2009. / Title from screen (viewed on December 1, 2009). Department of Cellular and Integrative Physiology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): B. Paul Herring, Anthony B. Firulli, Frederick M. Pavalko, Simon J. Rhodes. Includes vitae. Includes bibliographical references (leaves 138-149).

Thesis (Ph. D.)--University of Kentucky, 2003. / Title from document title page. Document formatted into pages; contains x, 192p. : ill. Includes abstract. Includes bibliographical references (p. 165-189).

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Physiology / Master / Master of Medical Sciences

Background: Regulation of vascular tone is complex. Various complementary signaling pathways causing contraction and relaxation of vascular smooth muscle take place to ensure proper blood flow within the vasculature. Mitogen activated protein kinase (MAPK) signaling cascade is observed to be one of the many signaling pathways that regulate vascular tone. Aim: This study examines the role of the following MAPK: mitogen-activated extracellular-regulated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and p38 MAPK in the regulation of relaxation in the endothelium and smooth muscle. Method: Isometric tension of isolated porcine coronary artery rings were measured with organ chamber setup. The effects of MEK inhibitor, PD98059 (30 μM), ERK inhibitor, U0126 (10 μM) and p38 MAPK inhibitor, SB203580 (10 μM), on relaxations induced by bradykinin (a vasodilating peptide), SKA-31 [an activator of small and intermediate conductance calcium-activated potassium channels (SKCa and IKCa,, respectively)], Deta NONOate (a nitric oxide donor) and forskolin (an adenylate cyclase activator) were examined in arteries with and without endothelium, contracted with an thromboxane A2 analog, U46619 (300 nM – 1 μM). In some experiments, rings were also incubated with the following pharmacological inhibitors, indomethacin (cyclooxygenase inhibitor, 10 μM), L-NAME (nitric oxide synthase inhibitor, 300 μM), TRAM34 (IKCa blocker, 1 μM), and UCL1684 (SKCa blocker, 1 μM), alone or in combination. Results: 1. Bradykinin-induced relaxation was potentiated by MEK and ERK inhibition but not by p38 MAPK inhibition. 2. SKA-31-induced relaxation was potentiated by MEK and p38 MAPK inhibition but not by ERK inhibition. 3. Deta NONOate-induced relaxation was potentiated by MEK, p38 MAPK inhibition, but not by ERK inhibition except in the presence of indomethacin, TRAM-34 plus UCL1684. 4. Forskolin-induced relaxation was potentiated by MEK and p38 MAPK inhibition, but not by ERK inhibition. Discussion: MAPK plays a role in regulating the vascular tone in both the endothelium and smooth muscle of porcine coronary arteries. MEK appears to have an inhibitory action on relaxation that is downstream of the generation of endothelium-derived nitric oxide, activation of IKCa and SKCa and activation of adenylate cyclase. ERK are unlikely to be the downstream target of MEK for inhibiting relaxation, in view of the lack of effects of its inhibitor on endothelium-derived hyperpolarizing factor (EDHF)-mediated and endothelium-independent relaxations. The involvement of ERK in relaxation pathways in the endothelium appears to be complicated, since U0126 caused opposing effects (inhibition and potentiation) on bradykinin-induced relaxation in the presence of indomethacin without and with L-NAME or TRAM-34 plus UCL1684. As inhibition of p38 MAPK results in potentiation of relaxations to all relaxing agents tested except bradykinin, this MAPK may have opposing action in the endothelium and smooth muscle; endothelial p38 MAPK may facilitate relaxation while smooth muscle p38 MAPK attenuates it. In conclusion, this study provided additional information on the influences of MEK, ERK and p38 MAPK on relaxation; this knowledge may contribute to the understanding of the mechanisms underlying the development of vascular disorders. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

No description available.

Arterial smooth muscle cells (SMCs) from the systemic and pulmonary circulations experience a broad range of oxygen concentrations under physiological conditions. The hypoxic response, however, has been inconsistent, with both enhanced proliferation and growth arrest being reported. This variability precludes a definitive conclusion regarding the role of oxygen tension in arterial disease. In the first part of this study, we determined if hypoxia elicits different proliferative and apoptotic responses in human aortic SMCs (HASMCs) incubated under conditions which do or do not result in cellular ATP depletion and whether these effects are relevant to vascular remodeling in vivo. Gene expression profiling was used to identify potential regulatory pathways. In HASMCs incubated at 3% O2, proliferation and progression through G1/S interphase are enhanced. Incubation at 1% O2 reduced proliferation, delayed G1/S transition, increased apoptosis and cellular ATP levels were reduced. In aorta and mesenteric artery from hypoxia exposed rats, both proliferation and apoptosis are increased after 48hrs. p53 and p21expression is differentially affected in HASMCs incubated at 1% and 3% O2. Hypoxia induces a state of enhanced cell turnover, conferring the ability to remodel the vasculature in response to changing tissue metabolic needs while avoiding the accumulation of mutations that may lead to malignant transformation or abnormal vascular structure formation. A unifying hypothesis in which events at the G1/S transition and apoptosis activation are coordinated by effects on p53, p21, their downstream effector genes and regulatory factors is proposed. Differences in the contractile responses of systemic and pulmonary arterial smooth muscle cells to hypoxia are well studied. Differences in proliferation and survival are anticipated because of differences in embryonal cell origin, oxygen concentrations within their respective microenvironments and in cellular energetics but these responses have not been directly compared. In the second part of the study, human pulmonary arterial SMCs (HPASMCs) proliferated at oxygen concentrations which inhibited cell growth in HASMCs. HPASMCs survived and maintained their intracellular ATP levels at levels of hypoxia sufficient to deplete ATP and induce apoptosis in HASMCs. In vivo studies in rats show proliferation and apoptosis in main or branch PASMCs only after 7 days of hypoxia. VSMCs are able to proliferate under hypoxic conditions as long as cellular ATP levels are maintained. HPASMCs have an enhanced capacity to maintain cellular energy status compared to HASMCs and hence their viability is preserved and the proliferative response predominates at lower oxygen concentrations.