Mohammed G. Kabir

Decreased endothelial NO synthase (eNOS)-derived NO bioavailability and impaired vasomotor control are crucial factors in cardiovascular disease pathogenesis. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a vascular disorder associated with ENDOGLIN (ENG) haploinsufficiency and characterized by venous dilatations, focal loss of capillaries, and arteriovenous malformations (AVMs). We report that resistance arteries from Eng+/- mice display an eNOS-dependent enhancement in endothelium-dependent dilatation and impairment in the myogenic response, despite reduced eNOS levels. We have found that eNOS is significantly reduced in endoglin-deficient endothelial cells because of decreased eNOS protein half-life. We demonstrate that endoglin can reside in caveolae and associate with eNOS, suggesting a stabilizing function of endoglin for eNOS. After Ca2+-induced activation, endoglin-deficient endothelial cells have reduced eNOS/Hsp90 association, produce less NO, and generate more eNOS-derived superoxide (O2-), indicating that endoglin also facilitates eNOS/Hsp90 interactions and is an important regulator in the coupling of eNOS activity. Treatment with an O2- scavenger reverses the vasomotor abnormalities in Eng(+/-) arteries, suggesting that uncoupled eNOS and resulting impaired myogenic response represent early events in HHT1 pathogenesis and that the use of antioxidants may provide a novel therapeutic modality.

AIMS: Mutations in the ALK1 gene, coding for an endothelial-specific receptor of the transforming growth factor-β superfamily, are the underlying cause of hereditary haemorrhagic telangiectasia type 2, but are also associated with familial pulmonary hypertension (PH). We assessed the lung vasculature of mice with a heterozygous deletion of Alk1 (Alk1(+/-)) for disease manifestations and levels of reactive O(2) species (ROS) implicated in both disorders. METHODS AND RESULTS: Several signs of PH, including elevated right ventricular (RV) systolic pressure leading to RV hypertrophy, reduced vascular density, and increased thickness and outward remodelling of pulmonary arterioles, were observed in 8- to 18-week-old Alk1(+/-) mice relative to wild-type littermate controls. Higher ROS lung levels were also documented. At 3 weeks, Alk1(+/-) mice were indistinguishable from controls and were prevented from subsequently developing PH when treated with the anti-oxidant Tempol for 6 weeks, confirming a role for ROS in pathogenesis. Levels of NADPH oxidases and superoxide dismutases were higher in adults than newborns, but unchanged in Alk1(+/-) mice vs. controls. Prostaglandin metabolites were also normal in adult Alk1(+/-) lungs. In contrast, NO production was reduced, while endothelial NO synthase (eNOS)-dependent ROS production was increased in adult Alk1(+/-) mice. Pulmonary near resistance arteries from adult Alk1(+/-) mice showed less agonist-induced force and greater acetylcholine-induced relaxation; the later was normalized by catalase or Tempol treatment. CONCLUSION: The increased pulmonary vascular remodelling in Alk1(+/-) mice leads to signs of PH and is associated with eNOS-dependent ROS production, which is preventable by anti-oxidant treatment.

OBJECTIVE: Loss-of-function mutations in genes coding for transforming growth factor-beta/bone morphogenetic protein receptors and changes in nitric oxide(*) (NO(*)) bioavailability are associated with hereditary hemorrhagic telangiectasia and some forms of pulmonary arterial hypertension. How these abnormalities lead to seemingly disparate pulmonary pathologies remains unknown. Endoglin (Eng), a transforming growth factor-beta coreceptor, is mutated in hereditary hemorrhagic telangiectasia and involved in regulating endothelial NO(*) synthase (eNOS)-derived NO(*) production and oxidative stress. Because some patients with pulmonary arterial hypertension harbor ENG mutations leading to haplo insufficiency, we investigated the pulmonary vasculature of Eng(+/-) mice and the potential contribution of abnormal eNOS activation to pulmonary arterial hypertension. METHODS AND RESULTS: Hemodynamic, histological, and biochemical assessments and x-ray micro-CT imaging of adult Eng(+/-) mice indicated signs of pulmonary arterial hypertension including increased right ventricular systolic pressure, degeneration of the distal pulmonary vasculature, and muscularization of small arteries. These findings were absent in 3-week-old Eng(+/-) mice and were attributable to constitutively uncoupled eNOS activity in the pulmonary circulation, as evidenced by reduced eNOS/heat shock protein 90 association and increased eNOS-derived superoxide ((*)O(2)(-)) production in a BH(4)-independent manner. These changes render eNOS unresponsive to regulation by transforming growth factor-beta/bone morphogenetic protein and underlie the signs of pulmonary arterial hypertension that were prevented by Tempol. CONCLUSIONS: Adult Eng(+/-) mice acquire signs of pulmonary arterial hypertension that are attributable to uncoupled eNOS activity and increased (*)O(2)(-) production, which can be prevented by antioxidant treatment. Eng links transforming growth factor/bone morphogenetic protein receptors to the eNOS activation complex, and its reduction in the pulmonary vasculature leads to increased oxidative stress and pulmonary arterial hypertension.

Perceiving granular material as a collection of particles, a constitutive law for granular material is derived based on a micromechanics approach. The constitutive model takes into account the mechanisms of sliding and separation of particles under large deformation. One of the obstacles for modeling particle sliding is the nonuniform strain field under large deformation. In this paper we tackle this problem by introducing a distributive law that describes the heterogeneous strain field. A brief review of the previous work on granular mechanics is presented followed by a description of the current approach. This approach treats the material at three levels, namely, representative unit, microelement and interparticle contact. On this basis the constitutive laws for each level are derived, and the overall stress‐strain relationship is expressed in terms of interparticle contact behavior. The unique features of the present theory are discussed to show its usefulness in comprehensive modeling of complex behavior for granular material.

A micromechanics‐based constitutive model for granular material is evaluated. The predicted stress‐strain behavior for idealized material is compared with that observed from experiments for sands. Under small strain conditions, the model capability is evaluated for predicting initial moduli, secant moduli, and damping ratio with the material is subjected to low‐amplitude loading. Under large strain conditions, the model capability is evaluated for predicting the stress‐strain strength behavior when the material is subjected to various stress paths. In the predictions, three material parameters are used to represent the stiffness and friction of the interparticle contact. Although the predictions are made for idealized spherical particles, the predicted behaviors are found to be remarkably similar to that observed for sands in experiments. The potential capability of the proposed constitutive theory is illustrated, and the model performance is discussed on various aspects of granular material behavior, such as stress‐induced anisotropy, path dependency, plastic flow, dilatancy, and noncoaxial behavior under rotation of principal stress.