RESISTANCE ARTERY REMODELING HYPERTENSION

描述（由申请人提供）：当大动脉肥大时

DESCRIPTION (provided by applicant): While large arteries hypertrophy in experimental renal and human hypertension, peripheral resistance is increased by inward, eutrophic remodeling of arterioles. Our long-term objective is to determine the mechanisms behind these two types of vascular remodeling. Our previous experiments suggest the hypothesis that circumferential wall stress, elevated by increasing blood pressure, is a major stimulus for hypertrophy of large arteries but this hypertrophic stimulus is prevented in arterioles by vasoconstriction. Sustained vasoconstriction leads to inward, eutrophic remodeling by rearrangement of the same cells around the smaller lumen. To test this hypothesis, isolated small mesenteric arteries (200-300 urn) mounted on micropipets in a tissue bath will be used to determine the initial signals in mechanotransduction of a pressure stimulus. The role of focal adhesion kinase (FAK), c-Src, the MAP kinases Erkl/2, iNK and p38 will be investigated by Western blotting with antibodies specific for the active form of the kinase. Confocal fluorescence microscopy will be used to locate the site of active forms of FAK and Src. Inhibitors will be used to determine if the initial mechanotransduction signal depends upon free radical production, activation of the PDGF-alpha receptor, or integrins recognizing the RGD motif. Production of superoxide anion and phosphorylation of the PDGF-alpha receptor also will be measured. The endothelium will be denuded in some arteries to determine its contribution to mechanotransduction and to the results of the assays performed on whole arteries. Isolated gracilis feeding arterioles (150 urn) will be used to determine if a chronic myogenic response can lead to inward, eutrophic remodeling over a 5-day period and whether this remodeling involves proliferation or apoptosis. Antisense oligomers for PDGF-A will be used to determine whether PDGF-A is essential for vascular wall hypertrophy in the one-kidney, one-clip hypertensive rat. Wall cross-sectional area will be determined by video-based image analysis of paraffin-embedded arteries. Proliferating cells will be detected by immunobistochemistry for BrdU incorporation and apoptotic cells by the ApopTag hi sftu TUNEL method. Other artery segments will be analyzed by RT-PCR for PDGF-A and PDGF-B mRNA, or quick frozen for SDS-PAGE and immunoblotting for PDGF-A and PDGF-B. These results could clarify the role of large arteries and resistance vessels in the development of hypertension as being adaptations to control wall stress and autoregulate blood flow rather than as a cause of hypertension. This information could also form the basis for more effective therapy to reverse structural changes in arterial walls that if unchecked can lead to vascular pathologies in target organs.