The contribution of resident vascular stem cells to arterial pathology

Abstract

Intimal accumulation of smooth muscle cells contributes to the development and progression of atherosclerotic lesions and restenosis following endovascular procedures. Arterial smooth muscle cells display heterogeneous phenotypes in both physiological and pathological conditions. In response to injury, dedifferentiated or synthetic smooth muscle cells proliferate and migrate from the tunica media into the intima. As a consequence, smooth muscle cells in vascular lesions show a prevalent dedifferentiated phenotype compared to the contractile appearance of normal media smooth muscle cells. The discovery of abundant stem antigen-expressing cells in vascular lesions also rarely detected in the tunica media of normal adult vessels stimulated a great scientific debate concerning the possibility that proliferating vascular wall-resident stem cells accumulate into the neointima and contribute to the progression of lesions. Although several experimental studies support this hypothesis, others researchers suggest a positive effect of stem cells on plaque stabilization. So, the real contribute of vascular wall-resident stem cells to pathological vascular remodelling needs further investigation. This review will examine the evidence and the contribution of vascular wall-resident stem cells to arterial pathobiology, in order to address future investigations as potential therapeutic target to prevent the progression of vascular diseases.

Keywords: Arterial wall; Intimal thickening; Resident stem cells; Smooth muscle cell heterogeneity; Smooth muscle cells.

Fig. 1

phenotypic heterogeneity of adult vascular smooth muscle cells. Rat aortic normal media SMCs (left column) display with the classical “hill-and-valley” confluent grow pattern when cultured in plastic dishes, a more dendritic shape with a marked extracellular matrix remodelling when cultured in collagen gel and display abundant α-smooth muscle actin (α-sm actin)-positive stress fibers in immunofluorescence (rhodamine, bottom). In contrast, neointimal VSMCs obtained fifteen days after ballooning (right column) display a monolayered and epithelioid appearance (top), grow in Indian files with bipolar conjunctions in collagen gel and contain very low amount of α-smooth muscle actin (bottom).

Fig. 2

Stem cell expression in rat aorta after injury and with aging. Serial immunostainings reveal (A) very rare cell are c-kit⁺ positive in normal 2 month-old rat aorta. (B) fifteen days after ballon injury, the majority of intimal and some of medial SMCs are c-kit⁺ positive. (C) Very rare SMCs are flt-1⁺ in normal 2 month-old rat aorta, but (D) the number of flt-1⁺ cells increases in 24-month old rat aorta.

Fig. 3

flt-1 expression and smooth muscle cell proliferation. Double immunostaining reveals that flt-1 expression (red) characterizes rat aortic bromodeoxyurinine+ proliferating SMC (arrow, black) in the tunica media three days after ballooning.