Sympathetic innervation promotes vascular smooth muscle differentiation

Abstract

The sympathetic nervous system (SNS) is an important modulator of vascular smooth muscle (VSM) growth and function. Several lines of evidence suggest that the SNS also promotes VSM differentiation. The present study tests this hypothesis. Expression of smooth muscle myosin (SM2) and ␣-actin were assessed by Western analysis as indexes of VSM differentiation. SM2 expression (normalized to ␣-actin) in adult innervated rat femoral and tail arteries was 479 Ϯ 115% of that in noninnervated carotid arteries. Expression of ␣-actin (normalized to GAPDH or total protein) in 30-dayinnervated rat femoral arteries was greater than in corresponding noninnervated femoral arteries from guanethidine-sympathectomized rats. SM2 expression (normalized to ␣-actin) in neonatal femoral arteries grown in vitro for 7 days in the presence of sympathetic ganglia was greater than SM2 expression in corresponding arteries grown in the absence of sympathetic ganglia. In VSM-endothelial cell cultures grown in the presence of dissociated sympathetic neurons, ␣-actin (normalized to GAPDH) was 300 Ϯ 66% of that in corresponding cultures grown in the absence of neurons. This effect was inhibited by an antibody that neutralized the activity of transforming growth factor-␤2. All of these data indicate that sympathetic innervation increased VSM contractile protein expression and thereby suggest that the SNS promotes and/or maintains VSM differentiation. endothelial cells; transforming growth factor-␤; ␣-actin; myosin VASCULAR SMOOTH MUSCLE (VSM) differentiation is critical for the normal development of blood vessels. VSMs must differentiate from the synthetic phenotype required for growth of blood vessels to the contractile phenotype required for appropriate regulation of blood pressure and blood flow. VSM differentiation is associated with increased expression of contractile proteins such as smooth muscle actin and myosin (12,14,15,17,20,21,24,28). In many cardiovascular diseases including hypertension, atherosclerosis, and ischemic heart disease, differentiated contractile VSM dedifferentiates to a more synthetic phenotype (1,13,20,23,28). This "developmental regression" can compromise cardiovascular function. The physiological and pathological mechanisms that modulate the differentiation of VSM are not well understood.The sympathetic nervous system is an important determinant of vascular growth and function (5,6,8,27,33). The effects of the sympathetic nervous system on VSM differentiation have not been studied extensively, but there is evidence to suggest that sympathetic neurons (SNs) promote or maintain VSM differentiation. Dimitriadou et al. (10) observed that sympathetic denervation produced morphological changes in VSM and suggested that these changes were characteristic of VSM dedifferentiation. Kacem et al. (19) found that VSMs in denervated arteries expressed more vimentin than corresponding innervated arteries. These authors suggested that vimentin was a marker for dedifferentiated VSM. The mechanisms of these effects were not investi...

The stress of maternal separation causes misprogramming in the postnatal maturation of rat resistance arteries

“…These experiments cannot exclude the possibility that suppression by ␣-adrenergic blockade is secondary to an effect elsewhere in the animal. However, in vitro experiments have shown that ␣ 1 -adrenergic signaling can directly program smooth muscle differentiation through autocrine transforming growth factor-␤ signaling (11), while in other cell types it couples to second messengers and transcriptional pathways, including calcium (nuclear factor of activated T cells), activator protein-1, cAMP (cAMP response element binding protein), and nuclear factor-B (17,46,60). In the present study, ␣-adrenergic blockade suppressed the normal developmental maturation of MA smooth muscle and stressinduced augmentation of this process.…”

Postinfarction healing dynamics in the mechanically unloaded rat left ventricle

“…First, it is well known that sympathetic sprouting is important for infarct healing and scar formation, especially in angiogenesis and lymphangiogenesis (3,4,20), whereas the murine HTx preparation is devoid of innervation and lacks communication with cervical ganglions and the central nervous system. Therefore, its potential impact on the inflammatory response and on cardiac neural stem cell function (10) during LV unloading cannot be clarified in the present work.…”

“…The I group was further divided into the in situ MI (I-infarct) group and in situ sham (I-sham) group. Surviving rats were killed on days 3,7,14, and 35 after the operations.…”

Impaired Autonomic Regulation of Resistance Arteries in Mice With Low Vascular Endothelial Growth Factor or Upon Vascular Endothelial Growth Factor Trap Delivery

“…Previous studies documented that cultured sympathetic neurons express VEGFRs and respond to VEGF by enhanced axon outgrowth and survival, 12 but so far, VEGF has not been reported to induce structural changes in prejunctional nerve terminals. Because autonomic nerve endings are known to release SMC-trophic factors, 24 a dysfunction of these nerve terminals may secondarily lead to SMC dedifferentiation. Indeed, activation of ␣ 1 -adrenoreceptors by noradrenaline stimulates SMC proliferation, 25 and sympathetic innervation increases vascular SMC contractile protein expression, 24 whereas sympathectomy results in a switch from a contractile to synthetic SMC phenotype.…”