Pituitary factors in blood plasma are necessary for smooth muscle cell proliferation in response to injury in vivo

Abstract

Intimai thickening in response to vascular injury is inhibited in animals previously subjected to hypophysectomy. We have investigated the nature and cell kinetics of this effect in a balloon catheter model of injury to the rat carotid artery. The ability of injury to stimulate [3H]thymidine labeling 48 hours after injury was almost completely eliminated in hypophysectomized (hypox) compared with control animals (0.1% versus 32.1%). Total DNA content of the developing neointima 14 days after injury was only 30% of the values found in ballooned carotid arteries of normal rats. If hypox rats were treated with recombinant human growth hormone, the proliferative response was not restored. There are two possible general explanations for the reduction of proliferative response in hypox animals: 1) that smooth muscle cells in the hypox animals have lost the ability to respond to the stimulus of injury or 2) that the ability of the smooth muscle cells to respond has not been reduced by prior hypophysectomy, but that the response itself requires the presence of pituitary-dependent factors. Transplantation experiments were performed in vivo to distinguish between these possibilities. Carotid arteries in inbred Lewis rats were excised 1 hour after balloon injury to give platelets the opportunity to adhere. These vessels were then transplanted from hypox into control animals and vice versa. At 48 hours, proliferation of smooth muscle cells in "control-to-hypox" transplants was 0.3% compared with 14.3% in "control-to-control" transplants, whereas vessels from hypox rats increased their indices to 4.8% if transplanted into control animals. This indicates that the ability of the smooth muscle cells to proliferate depends on their hormonal environment after injury rather than on the past history or state of the smooth muscle cells. This conclusion is supported by in vitro experiments that show no difference in the growth properties of primary cultures of carotid smooth muscle cells from control and hypox animals but that demonstrate less growth-promoting activity in plasma-derived serum from hypox animals. We conclude that one or more hormonal factors in the plasma, dependent on the pituitary, are required for smooth muscle proliferation in response to injury and that hypophysectomy does not produce a stable change in the properties of the smooth muscle cells themselves.