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Using a combination of in-vitro and in-vivo experimental techniques, the maturational changes in arteriolar structure and blood flow regulation were explored in the spinotrapezius muscle of weanling, juvenile and mature rats. In the first study, morphometric analysis of the arteriolar network architecture revealed that mean arcade segment length and arcade loop circumference had significantly increased from weanling to mature groups, whereas total number of arcade arteriole segments remained fairly constant. The number of transverse arteriole subnetworks per muscle remained constant from weanling to mature rats, but there were significant increases in total number of vessels in each branch order, total subnetwork length, and mean length of individual branches. Using intravital microscopy, the subsequent experiments revealed that as the animals matured resting and passive arteriolar diameters and resting volume flow increased whereas resting arteriolar wall shear rates decreased. NOS inhibition by L-NMMA had no effect on arteriolar diameters in weanling animals but significantly reduced arteriolar diameters in older groups. Arteriolar responses to iontophoretically-applied ACh or SNP were dose-dependent but the magnitude of dilation to either did not differ among age groups. In the presence of L-NMMA, ACh-induced vasodilation was reduced less in mature rats than in weanling rats, but could be further reduced by cyclooxygenase inhibition. Sympathetic nerve stimulation induced frequency-dependent arteriolar constrictions that were greater in juvenile than weanling rats and were abolished by TTX or phentolamine in both groups. L-NMMA significantly reduced resting arteriolar diameters in juvenile rats, but was ineffective in weanling rats, whereas meclofenamate significantly reduced resting arteriolar diameters in both age groups. Neither blocker affected arteriolar responses to sympathetic stimulation in either group. Taken together, the results suggest that significant increases in arteriolar network size occur during juvenile maturation due to remodeling of pre-existing arterioles with angiogenesis occurring in terminal arteriolar segments. Concomitantly, the overall responsiveness to ACh remains unaltered, but NO release in response to ACh decreases and prostaglandins play an increasingly important role in this response as growth continues. Arteriolar responsiveness to sympathetic nerve activity increases from weanling to juvenile animals, and is unaltered by prostaglandin activity or the maturational onset of endogenous NO release.