Various cardiovascular pathologies are associated with vascular smooth muscle cell (VSMC)
hypertrophy and elevated plasma
leptin levels. We used the rat portal vein (RPV) cultured for three days to investigate the effect of mechanical stretch on autocrine secretion of
leptin and the effect of exogenous
leptin (3.1 nM) on VSMC. Stretching the RPV significantly up-regulated
leptin production by greater than 100-fold and
leptin receptor expression by up to 10-fold. In addition, stretch increased tissue weight by 23 +/- 1.3 and 30 +/- 1% (P < 0.05), respectively, in the absence or presence of
leptin, although this was significantly attenuated by an antileptin antibody (166 ng/ml). Unstretched RPV weight decreased by 7.5 +/- 1.8% in the absence of
leptin, whereas in the presence of
leptin, weight increased by 6.5 +/- 1.8% (P < 0.05). VSMC size and [3H]
leucine incorporation rates were significantly increased by
leptin in stretched and unstretched tissues.
Leptin-induced
hypertrophy was associated with significant
extracellular signal-regulated kinase (ERK1/2) activation as well as increased expression of
angiotensinogen, the
angiotensin type 1 receptor as well as
preproendothelin-1, and the
endothelin type A receptor, whereas ERK inhibition or inhibition of either the
angiotensin II or
endothelin-1 systems at both the synthesis and receptor levels blocked the hypertrophic response. The effects of
leptin were also completely blocked by the
cholesterol-
chelating agent methyl-beta-cyclodextrin. Therefore, our study demonstrates stretch-dependent
leptin release and a direct hypertrophic effect of
leptin on RPV, the latter likely dependent on intact
cholesterol-rich membrane microdomains and locally produced paracrine factors.