Mail server is detecting port 25 in 'watchdog'. But sometimes, detecting port is inacurate and certain service doesn't use port (example php-fpm).
Restarting does not make qmail down or vpopmail but nobody would be able to login to his mail account.
It's because vpopmail uses some permanent connections in MySQL and when you restart MySQL it's still looking for these old connections.
Some solution is to add timeout to my.cnf but this will make some troubles with logging in as well. Another solution is to make a test script which will be logging to one of test accounts and if login is failed then it will execute qmailctl stop; qmailctl start