The clinical need for the design of small-diameter vascular substitutes with high patency rates has never been so urgent as nowadays. Mechano-compatibility is widely known as one of the main key parameter for the design and the development of highly-patent vascular substitutes independently of their nature, i.e., arterial prostheses, arterial grafts or tissue-engineered blood-vessel. In this work, we attempt to target mechano-compatibility of cylindrical scaffolds for vascular tissue engineering by a computational model based on the composite theory associated with finite element and genetic algorithm. Then, cylindrical composite scaffolds were fabricated from gelatine (matrix) and silk (reinforcement) to experimentally validate theoretical results obtained by the implemented computational model. Finally, the compliance of the scaffolds was measured by an in-house developed specific device. Results show that the computational predictions from numerical simulation are in good agreement with the measurements obtained form the experimental tests. Therefore, the proposed computational model represents a valid tool to assist biomaterial scientists during the design of composite scaffolds, and especially in targeting their mechanical properties.