In fetal sheep, umbilical responsiveness to ANG II exceeds systemic vascular responsiveness. Fetal systemic vascular smooth muscle (VSM) exhibits an immature phenotype with decreased contractile protein contents, low 200-kDa myosin heavy chain (MHC) SM2, and significant nonmuscle MHC-B expression, whereas umbilical VSM phenotype is incompletely described. We tested the hypothesis that differences in vascular responsiveness could reflect dissimilarities in VSM phenotype. Actin, MHC, MHC isoforms, and active stresses were compared in strips of femoral arteries and aorta from near-term fetal ( n = 12) and adult ( n = 12) sheep to those in external and intra-abdominal umbilical arteries. Actin contents in fetal femoral artery and aorta were less ( P ≤ 0.006) than in external umbilical artery (7.37 ± 1.4 and 7.53 ± 0.7 vs. 21.6 ± 2.2 μg/mg wet wt, respectively) as were MHC contents (3.17 ± 0.4 and 2.84 ± 0.3 vs. 7.16 ± 0.7, respectively). Whereas 204- and 200-kDa MHC were expressed equally in fetal systemic arteries, umbilical and adult arteries predominantly expressed the 204-kDa isoform (SM1); only fetal systemic VSM expressed MHC-B. Fetal systemic artery stresses and myosin light chain phosphorylation were less than those in umbilical and adult arteries ( P < 0.001). Compared with umbilical and adult arteries, fetal systemic VSM is biochemically and functionally immature and thus umbilical VSM demonstrates precocious maturation resembling adult VSM in protein expression and function.
Abstract-Tenascin-C (TN-C) is an extracellular matrix (ECM) protein expressed within remodeling systemic and pulmonary arteries (PAs), where it supports vascular smooth muscle cell (SMC) proliferation. Previously, we showed that A10 SMCs cultivated on native type I collagen possess a spindle-shaped morphology and do not express TN-C, whereas those on denatured collagen possess a well-defined F-actin stress fiber network, a spread morphology, and they do express TN-C. To determine whether changes in cytoskeletal architecture control TN-C, SMCs on denatured collagen were treated with cytochalasin D, which decreased SMC spreading and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling effectors required for TN-C transcription. Next, to determine whether cell shape, dictated by the F-actin cytoskeleton, regulates TN-C, different geometries of SMCs (ranging from spread to round) were engineered on denatured collagen: as SMCs progressively rounded, ERK1/2 activity and TN-C transcription declined. Because RhoA and Rho kinase (ROCK) regulate cell morphology by controlling cytoskeletal architecture, we reasoned that these factors might also regulate TN-C. Indeed, SMCs on denatured collagen possessed higher levels of RhoA activity than those on native collagen, and blocking RhoA or ROCK activities attenuated SMC spreading, ERK1/2 activity, and TN-C expression in SMCs on denatured collagen. Thus, ROCK controls the configuration of the F-actin cytoskeleton and SMC shape in a manner that is permissive for ERK1/2-dependent production of TN-C. Finally, we showed that inhibition of ROCK activity suppresses SMC TN-C expression and disease progression in hypertensive rat PAs. Thus, in addition to its role in regulating vasoconstriction, ROCK also controls matrix production. (Circ Res. 2006;99:837-844.)Key Words: tenascin-C Ⅲ smooth muscle Ⅲ ROCK Ⅲ pulmonary hypertension A dult vascular smooth muscle cells (SMCs) reside within a type I collagen-enriched extracellular matrix (ECM) that helps to maintain the majority of these cells in a nonmotile, growth-arrested, and differentiated state. 1-4 Following vascular injury, however, ECM-degrading matrix metalloproteinases (MMPs) remodel the preexisting ECM to create a tissue microenvironment that is conducive for SMC proliferation, migration, and survival. [3][4][5] Understanding how alterations in adhesive interactions within the vascular ECM modify SMC behavior, therefore, represents an important question in vascular pathobiology.Tenascin-C (TN-C) is an ECM glycoprotein induced within remodeling hypertensive pulmonary arteries (PAs), 6 -10 as well as in systemic, obliterative vasculopathies, [11][12][13] where it supports vascular SMC proliferation, migration, and survival. 4,14,15 In keeping with the idea that TN-C plays a direct role in promoting vascular disease, studies using TN-C null mice demonstrate that these animals are refractory to neointimal hyperplasia after aortotomy. 11 Further, blocking TN-C expression in cultured hypertensive rat PAs induces ...
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