Mechanosensing in the vascular wall - the role of cellular microdomains in vascular remodeling

Sammanfattning: The vascular wall has a remarkable capacity to adapt to mechanical forces exerted by the intraluminal blood pressure and flow. This includes rapid change in contractile tone as well as chronic alteration of vessel structure if the stimulus persists. Stretch of the intact blood vessel wall promotes growth and contractile differentiation. The molecular mechanisms involved are not well defined, but contractile differentiation has been suggested to be mediated by polymerization of the cytoskeletal protein actin. Part of the machinery that signals growth may be assembled in membrane invaginations termed caveolae, and a role for caveolae in mechanosensing has accordingly been proposed. The studies summarized in this thesis aimed to determine the role of these two cellular domains in mechanosensitive signaling in the intact vascular wall using rat or mouse portal veins as well as carotid and small mesenteric arteries.

In the portal vein, we found that stretch promotes contractile differentiation via Rho activation and actin polymerization. An intact actin cytoskeleton is required for stretch-induced synthesis of smooth muscle specific marker proteins and for global protein synthesis. We also found that stabilizing actin filaments produced the same effects as stretch on protein synthesis. Stretch dependency of growth and differentiation was maintained in mice lacking caveolin-1 and vascular caveolae. In arteries from these mice, a reduced myogenic tone was observed, which was mainly caused by excessive nitric oxide (NO) production. Blood pressure was however maintained in vivo despite increased NO production. Maintenance of blood pressure in the setting of increased NO production could be due to increased alpha1-adrenergic contraction, hypertrophic remodeling and increased plasma volume.

In summary, the data suggest that stretch stimulates polymerization of actin, which is necessary for expression of smooth muscle differentiation markers and growth of the intact vascular wall. On the other hand, stretch-induced growth and differentiation is not dependent on caveolin-1 or caveolae, which may however play a role for contractile responses to mechanical stimuli.